Are there any serious side effects to GLP-1 agonists such as Ozempic?

In a previous post, I explained the differences between Ozempic and Wegovy. They share the same active ingredient, the GLP-1 agonist semaglutide, but are approved (and marketed) for different conditions: type II diabetes and weight loss, respectively.

One topic I did not touch upon in depth was the side effects. The good news is that the clinical trials did not reveal any serious issues with either medicine, or more generally the class of GLP-1 agonists that stimulate insulin secretion along with other beneficial properties.

The Ozempic website lists the following most common side effects of the drug:

• Nausea
• Diarrhea
• Stomach (abdominal) pain
• Vomiting
• Constipation

These are understandable given that semaglutide is known to slow gastric emptying and digestion in general. One consequence is reducing hunger and amount eaten resulting in lower weight and blood glucose. Overall these side effects are not considered serious, and many tend to go away after a short period of time.

The clinical trials enrolled thousands of patients over a several year period. But now that Ozempic (and Wegovy) are widely prescribed to millions of patients for an extended period of time, the question is whether any more serious side effects have emerged.

A new perspectives in JAMA explored this issue citing new studies. The review focused on more serious adverse events, and they fall into two categories: digestive problems and unexpected complications arising during anaesthesia. 

The former is consistent with the mechanism of action of semaglutide and other GLP-1 agonists, and are associated with more severe presentations of the common symptoms listed above. For example, the slowing of gastric emptying may be connected to the pancreatitis because impeded digestion may result in the build up of digestive enzymes in the pancreas leading to inflammation (Figure 1). 

More specifically, the review highlighted a recent analysis in JAMA that estimated the risk of serious stomach disorders from certain GLP-1 agonists including semaglutide. The researchers took advantage of a large health claims database to sample the claims of 16 million patients, and they found:

“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. The absolute risks in the GLP-1 group, however, were all about 1% or less per year of GLP-1 use. And semaglutide and liraglutide were not associated with biliary disease, which affects the gallbladder and bile production.

Acute pancreatitis and acute gallbladder disease are known adverse effects of GLP-1 agonists and are listed on the labels for all formulations of semaglutide and liraglutide. But study author Mahyar Etminan, PharmD, an epidemiologist at the University of British Columbia in Vancouver, said in an interview that gastroparesis and bowel obstruction are “a bit more unheard of.”

According to Wikipedia, gastroparesis, "is also called delayed gastric emptying, is a medical disorder consisting of weak muscular contractions (peristalsis) of the stomach, resulting in food and liquid remaining in the stomach for a prolonged period of time. [...] Symptoms include nausea, vomiting, abdominal pain, feeling full soon after beginning to eat (early satiety), abdominal bloating, and heartburn."

Bowel obstruction, "also known as intestinal obstruction, is a mechanical or functional obstruction of the intestines which prevents the normal movement of the products of digestion." Thus, by slowing gastric emptying and overall digestion, semaglutide mimics the effects and symptoms of gastroparesis and bowel obstruction, also increasing their likelihoods.

The 9 fold increased risk of pancreatitis, 4 times risk of bowel obstruction, and 3 times greater risk of gastroparesis are all striking numbers that affected as many as 1% of patients in the health claims database. The comparisons were made between those who took semaglutide or liraglutide versus the control group which took bupropion-naltrexone, "a fixed-dose combination medication for the management of chronic obesity in adults" (Wikipedia) which possesses a totally different mechanism of action from GLP-1 agonists.

A second source of concern has been raised by anaesthesiologists. In particular, the anaesthesiology community has reported instances of pulmonary aspiration, which involves the inhaling of the stomach's contents into the lungs during anaesthesia, which can lead to infections and pneumonia. Although uncommon, it can be life-threatening, and as a result, doctors advise not eating solid foods for 6 hours and avoiding clear liquids for 2 hours prior to an operation.

GLP-1 agonists such as semaglutide can exacerbate this risk presumably by slowing the emptying of the stomach. Recent scientific journal reports highlighted cases of individuals on GLP-1 agonists experiencing aspiration of food during anesthesia. These cases were notable for the significant amount of stomach contents regurgitated despite patients adhering to fasting guidelines.

In June, the American Society of Anesthesiologists issued a cautionary statement, along with revised recommendations. They advised against using daily GLP-1 agonists on the day of elective surgery and suggested stopping weekly versions, like Wegovy and Ozempic, a week before the procedure.

Taken together, some caution should be exercised when considering the benefits versus risks of taking Ozempic or Wegovy (semaglutide). Many of the common side effects listed above tend to go away in a short period of time (e.g. a few weeks) as the body becomes accustomed to the drugs. Also, doctors will slowly ramp up the dose while monitoring for any side effects. 

Although a very serious condition, pancreatitis is not usually deadly; most cases are acute (temporary) although some can be chronic (long-lasting). According to the Cleveland Clinic website, "[m]ost people with acute pancreatitis will recover completely in a few days with supportive care." If the pancreatitis persists, then the patient can be permanently moved off the drug. 

The benefits of semaglutide are significant for treating diabetes, weight management, cardiovascular health, and even cancer, but they do not apply to everyone. According to one statistic, 15% of people will lose only 5% or less of their body weight compared to the average weight loss of 16% on Wegovy. So the final decision should be patient-specific.

Figure 1. Pancreatitis is the inflammation of the pancreas. As shown in the graphic, the pancreas and liver share a common bile duct that delivers digestive enzymes to the small intestine. Any blockage or impeded flow through this duct can cause the build up of digestive enzymes in the pancreas leading to inflammation (Cleveland Clinic).