Widely prescribed drugs for weight loss and diabetes, such as GLP-1 receptor agonists (GLP-1RAs) and dual incretin receptor agonists like tirzepatide, are known for their effectiveness in reducing body weight and managing blood glucose levels. However, a recent review in the Journal of Clinical Investigation has outlined several side effects and rare risks associated with these medications that clinicians should monitor over time.
GLP-1RAs work by activating receptors primarily located in the brain, pancreas, and gastrointestinal tract. While they help control blood sugar and reduce appetite, these drugs can also lead to unwanted effects. "Central mechanisms by which peripheral GLP-1RAs may reduce appetite or induce nausea. Peripheral GLP-1 or GLP-1RAs may interact with appetite-regulating regions of the brain via gaps in the blood-brain barrier, via tanycyte uptake, or indirectly via the nodose ganglia. The effects to slow gastric emptying, induce nausea, and reduce energy intake are independent," according to the review article.
Gastrointestinal issues are among the most frequently reported side effects. Data from 39 randomized controlled trials indicate increased risks of vomiting, nausea, constipation, and diarrhea among non-diabetic users compared to placebo. In patients with type 2 diabetes (T2D), nearly one-fifth experienced nausea when using GLP-1RAs.
Tirzepatide acts on both GIP and GLP-1 receptors and has shown greater effectiveness than selective GLP-1RAs for weight loss and glucose lowering but carries a similar range of adverse events. Some studies suggest tirzepatide users face slightly higher rates of vomiting than those taking semaglutide.
There is also evidence that delayed gastric emptying caused by these drugs might complicate certain medical procedures due to retained stomach contents. Some analyses have found an increased risk of gallbladder disease with GLP-1RA therapy.
Earlier fears about links between these drugs and acute pancreatitis or pancreatic cancer have been largely eased by long-term studies that do not show a causal relationship; however, ongoing monitoring is still advised.
Concerns regarding medullary thyroid carcinoma arose after rodent studies showed changes in thyroid C cells following liraglutide treatment. While this effect is clear in rodents, human data remain mixed: "Data from France suggest a higher risk of medullary thyroid carcinoma in people treated with GLP-1RAs compared to other glucose-lowering agents." A meta-analysis also reported cases among patients using these medications but emphasized that absolute event numbers are low.
Eye health is another area under investigation. One trial linked semaglutide use to more retinopathy complications among individuals who already had advanced eye disease at baseline; further research is needed to determine if there is a direct cause-and-effect relationship.
Neuropsychiatric outcomes have produced mixed findings as well. "A large retrospective study found a two-fold increased risk of anxiety and suicidal behavior and a three-fold increased risk of major depression among GLP-1RA users." Other studies have suggested possible antidepressant benefits or no link at all between these medications and serious psychiatric effects such as suicide or psychosis.
Experts stress the importance of improved pharmacovigilance—ongoing safety monitoring—and standardized reporting practices to better understand potential risks associated with individual therapies across different patient groups including older adults or those with kidney disease.
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