[11] The main side effects of exenatide use are gastrointestinal in nature, including acid or sour stomach, belching, diarrhea, heartburn, indigestion, nausea, and vomiting.

[12] Drug interactions listed on the package insert include delayed or reduced concentrations of lovastatin, paracetamol (acetaminophen), and digoxin, although this has not been proven to alter the effectiveness of these other medications.

In response to postmarketing reports of acute pancreatitis in patients using exenatide, the US Food and Drug Administration (FDA) added a boxed warning to the labeling of Byetta in 2007.

Eli Lilly has stated the drug causes an increase in thyroid problems in rats given high doses.

[19] In March 2013, the FDA issued a Drug Safety Communication announcing investigations into incretin mimetics due to findings by academic researchers.

[27] During the early 1980s, Jean-Pierre Raufman worked as a postdoctoral researcher at the National Institutes of Health for John Pisano, an "eccentric biochemist" who specialized in collecting venoms from various animals and looking for novel substances that could affect human physiology.

[30] When Raufman gave a lecture about his findings,[30] his research piqued the curiosity of John Eng, an endocrinologist at the Veterans Administration Medical Center in New York City.

[28][29] Eng had trained under Rosalyn Sussman Yalow, who shared the 1977 Nobel Prize in Physiology or Medicine for development of the radioimmunoassay technique.

[28][30] This was an enormously significant clinical finding, because it was GLP-1's extremely short half-life which had defeated earlier attempts to turn that substance into a drug.

[28][30] Attempts to bypass that issue by infusing patients in clinical tests with very high doses of GLP-1—in order to overcome its rapid metabolism in the bloodstream—had produced extremely severe nausea, followed by immediate vomiting.

[38] In 2016, work published showing that it can reverse impaired calcium signalling in steatotic liver cells, which, in turn, might be associated with proper glucose control.

[40] A 2025 study that randomly assigned Parkinson’s patients to receive exenatide, a drug related to Ozempic, found no evidence that it slowed disease progression or provided any benefit after 96 weeks.

[41] The research, in The Lancet, showed no improvements in patient symptoms, brain scans, or any specific subgroup—regardless of how the data was analyzed, the outcome remained unchanged.