- Moderate to high quality evidence from a comprehensive review on non-cardiometabolic outcomes strengthens the association between GLP-1 therapies and risks of nausea, vomiting, and diarrhea.
- High-quality evidence indicated a possible protective relationship between GLP-1 drugs and infection-related outcomes, particularly serious infections.
- Exploratory signals also suggested a potential risk reduction for fractures, acute respiratory disease, and all-cause dementia.
GLP-1 drugs showed a range of potential benefits and safety concerns in a comprehensive review of non-cardiometabolic outcomes, although data quality remained limited for many.
Among 60 meta-analyses assessing 116 non-cardiometabolic outcomes, some of the most consistent indications were for adverse gastrointestinal events based on moderate or high quality evidence. This included a higher odds of nausea (OR 2.47, 95% CI 1.84-3.34), vomiting (OR 2.78, 95% CI 1.91-4.06), and diarrhea (OR 1.94, 95% CI 1.52-2.49), Yongzhe Li, MD, PhD, of the First Hospital of China Medical University in Shenyang, and colleagues reported. jama network open.
High-quality, solid evidence also suggested possible protective associations against infection-related outcomes, particularly for serious infections (OR 0.89, 95% CI 0.87–0.92).
Other indications also emerged in fracture, respiratory, neurological, psychiatric and endocrine outcomes. Despite reaching significance, most of the pooled results did not reach the predefined high-confidence threshold, leaving the associations exploratory and hypothesis-generating.
“Clinically, gastrointestinal adverse events are well recognized with GLP-1 receptor agonists, and our results confirm these as the most consistent and robust indications,” Li said. Medpage Today.
“What was more notable, however, was that for many other non-cardiometabolic outcomes, particularly those that have received recent attention – such as infections, respiratory disease and cancer-related outcomes – the evidence was often suggestive based on limited reliability,” they continued. “This reinforces the distinction between emerging signals and high-certainty evidence.”
Some exploratory associations included reduced odds of fracture, acute respiratory disease, and all-cause dementia. Other indications link GLP-1 drug use to higher prospects for resolution of steatohepatitis, gastroesophageal reflux disease, gallstones or biliary diseases, and thyroid disease associated with metabolic dysfunction.
Lee cautioned that not all statistically significant findings should be considered medically actionable.
“For GLP-1 receptor agonists, gastrointestinal adverse events are consistent and expected. However, for many other outcomes … the current evidence should be interpreted with caution,” they explained. “Clinicians should avoid overinterpreting early signals and continue to rely primarily on well-established cardiometabolic benefits when making treatment decisions.”
“In particular, any identified safety signals should prompt nuanced, individualized risk-benefit discussion and targeted monitoring – particularly for symptomatic patients or those with high-risk clinical profiles – rather than routine changes in GLP-1 receptor agonist prescribing patterns or monitoring protocols,” the team said. “GLP-1 receptor agonists remain the cornerstone of antidiabetic therapy but should not be misinterpreted as a panacea.”
Lee called for large-scale, long-term randomized trials and well-designed real-world studies to clarify whether these suggested associations translate into meaningful clinical benefits or risks.
The comprehensive review included 1,751 randomized clinical trials with more than 3.5 million participants. Studies were identified by a systematic search of databases until January 2026; Most were published within the last decade.
The majority of the study population (71.7%) included people with type 2 diabetes and one-third included people with obesity. The follow-up period ranged from 3 months to 5.4 years or more.
Lee and co-authors graded evidence certainty based on the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. The reliability of the evidence was classified as strong (Class I), highly suggestive (Class II), suggestive (Class III), weak (Class IV), or non-significant, depending on certain factors such as the number of trial participants and the extent of statistical significance.
“This allowed us to differentiate between findings that are statistically significant and those that are really robust and clinically reliable,” Lee explained. “In this sense, our work helps advance the field from signal detection to evidence evaluation.”
Evidence regarding cancer risks was inconclusive. While preclinical data have raised concerns about thyroid cancer, the researchers noted that the relevance of these findings to humans “remains unconfirmed.”
Because many non-cardiometabolic outcomes were recorded as adverse events rather than predefined endpoints in the study, the data may be susceptible to misclassification and reporting bias. Other limitations include the lack of stratification by GLP-1 drug dose or duration of treatment.
