GLP-1 agonists are a class of drug usually prescribed to help type II diabetics control their blood sugar. Doctors have increasingly been inspired to offer this class of drug for obesity due to the rise in popularity of Ozempic. Ozempic is the most well-known brand of GLP-1 agonist. In October 2023, University of British Columbia (UBC) researchers led by Dr. Mahyar Etminan reported in the medical journal, JAMA, that GLP-1 receptor agonists like semaglutide (Ozempic), or liraglutide (Victoza) cause significantly more adverse events than do other classes of weight loss drugs like bupropion-naltrexone (Contrave).1
Think Twice
Etminam and his team warn that while GLP-1 agonists are very effective as a diabetes medication, non-diabetics tempted to use them for weight loss should think carefully. They must consider whether losing weight quickly is worth the risk of developing pancreatitis, gastroparesis, or bowel obstruction.
The researchers found that people using GLP-1 agonists to battle the bulge were nine times more likely to suffer from pancreatitis than people using bupropion-naltrexone. The risk of developing gastroparesis was quadrupled in people employing GLP-1 agonists. GLP-1 agonist users were three times more likely to suffer from bowel obstructions.1
Until recently, a typical weight loss clinical trial for GLP-1 receptor agonists would follow a few hundred patients for a year.2 The focus of the trial would be on short-term side effects and how well the drug worked to keep off the kilograms. Gastroparesis, bowel obstruction and pancreatitis happen more frequently in people with obese body mass index. This means a year is too short a period to measure whether the drug was increasing the incidence. Those people could have developed the complication anyway, or perhaps it would take a few years for the drug to contribute. This is one of the first longer-term studies into the safety of Ozempic and similar drugs.
Fueling the Fire
The results of the UBC report found that while the three conditions do occur with some frequency in obese patients, using GLP-1 agonists significantly increased the risk that a person would become unwell.
Pancreatitis, gastroparesis and bowel obstruction are serious conditions. Pancreatitis is an extremely painful ailment and a particular concern in people at risk of developing type II diabetes. If you already have problems regulating your blood glucose, damage to your pancreas can only add fuel to the fire.3
Gastroparesis arises when food doesn’t empty from the stomach as quickly as it should. This can cause physical discomfort, vomiting, malnutrition and make glucose harder for your body to regulate. Some patients form a solid mass of compacted undigested food called a bezoar. These clumps of food can cause ulcers, bleeding and blockages in your gut. Diabetes is the most common cause of gastroparesis.4 Bowel obstructions often need surgery and can be life threatening if the blockage develops complications.5
Insurance Investigators
The researchers examined over 16 million American insurance records from the PharMetrics Plus for Academics database (IQVIA). They pulled out the anonymized histories of all patients prescribed semaglutide or liraglutide (the most widely used GLP-1 agonists) and bupropion-naltrexone (a weight-loss drug unrelated to GLP-1 agonists) between 2006 and 2020. Then from this group, they picked all the people who had been diagnosed as obese (BMI over 30). Of these subjects, they excluded anybody with a diabetes diagnosis or prescribed any drug for diabetes. They were left with 4,144 liraglutide, 613 semaglutide, and 654 bupropion-naltrexone users. Bupropion-naltrexone targets impulse control but not blood glucose levels. It helps with weight loss by making eating feel a little bit less rewarding. Based on their medical records, they assumed that these patients were prescribed GLP-1 agonists for weight loss.
Because they had the long-term histories of these patients, researchers could investigate how patients fared over several years. When they compared the records of patients prescribed GLP-1 agonists, they found significantly more cases of pancreatitis, gastroparesis and bowel obstruction than in people who used bupropion-naltrexone.
Scaling the raw numbers allowed the researchers to compare the numbers in terms of “patient-years.” In this study they measure the “risk,” in patient-years. So if you took a drug for five years, the chances of an outcome would be five times higher than someone who took it for one year. A thousand people taking it for one year would have the same chance of an event as 33 people using it for 30 years. This scaling allowed the researchers to compare the results of using semaglutide for six years with using liraglutide for ten years.
Triple Threat
They ultimately uncovered that 3.3 obese people in every 1,000 patient-years, would develop gastroparesis. If those obese patients used a GLP-1 agonist to try to lose weight, the incidence of gastroparesis would increase to around eight people per 1,000 patient-years. Likewise GLP-1 agonists upped cases of bowel obstruction from 1.7 people per 1,000 patient-years to 8.1 per 1,000 patient-years and pancreatitis from one in a thousand patient-years to around 7.5 people per 1,000 patient-years.
Handle With Care
Overall the risk of developing one of the conditions is low, at less than 1%. Yet, if you consider how many individuals might plan to use GLP-1 to control their appetite, that’s an awful lot of people. It also means that the longer you use the drug for any reason, the more likely you are to be one of that 1%. The overall health benefit from using GLP-1 agonists for diabetes is great enough that the advantages outweigh the risk of illness. It’s not yet clear whether non-diabetics who use this drug for weight loss would have the same risk to benefit balance.
These drugs are an excellent intervention for diabetes and could revolutionize treatment of metabolic syndrome. It is, however, always important to approach risk in an informed manner.
References
1 Sodhi M, Rezaeianzadeh R, Kezouh A, Etminan M. Risk of Gastrointestinal Adverse Events Associated With Glucagon-Like Peptide-1 Receptor Agonists for Weight Loss. JAMA. 2023;330(18):1795-1797. doi:10.1001/jama.2023.19574
2 Rubino DM, Greenway FL, Khalid U, et al. Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on Body Weight in Adults With Overweight or Obesity Without Diabetes: The STEP 8 Randomized Clinical Trial. JAMA. 2022;327(2):138-150. doi:10.1001/jama.2021.23619
3 Śliwińska-Mossoń M, Bil-Lula I, Marek G. The Cause and Effect Relationship of Diabetes after Acute Pancreatitis. Biomedicines. 2023;11(3):667. doi:10.3390/biomedicines11030667
4 Definition & Facts for Gastroparesis – NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. Accessed April 24, 2024. https://www.niddk.nih.gov/health-information/digestive-diseases/gastroparesis/definition-facts
5Smith DA, Kashyap S, Nehring SM. Bowel Obstruction. In: StatPearls. StatPearls Publishing; 2024. Accessed April 24, 2024. http://www.ncbi.nlm.nih.gov/books/NBK441975/
