GLP-1 Receptor Agonists May Improve Survival, Reduce irAEs in ICI-Treated Patients

Concurrent use of a glucagon-like peptide-1 receptor agonist (GLP-1 RA) with immune checkpoint inhibitor (ICI) treatment may be associated with significantly improved long-term survival among patients with cancer, according to a multi-institutional real-world cohort study presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting.

Further, patients receiving ICIs may experience a reduced burden of immune-related adverse events (irAEs) because of immune-modulatory protection from the GLP-1 RAs, Salman Jajja, MD, noted.

“The protective trends were consistent across all follow-ups of 3 years and 5 years, and these findings suggest a potential synergy or projective effect of GLP-1s on immunotherapy settings,” Jajja, of New York Medical College, Landmark Medical Center, Woonsocket, Rhode Island, said during a presentation of the real-world data.

What effect did GLP-1 use have on overall survival after ICI treatment?

The analysis drew on the TriNetX Research Network, a federated electronic health record database spanning 113 health care organizations. Adult patients with solid and hematologic malignancies who were treated with PD-1/PD-L1, or CTLA-4 inhibitors were identified and stratified by concurrent GLP-1 RA exposure.

Jajja explained that GLP-1 RAs are increasingly prescribed for metabolic comorbidities and weight management in patients with cancer; however, their impact on survival and irAEs remains poorly characterized. Further, no large-scale, real-world analysis has evaluated this drug interaction.

Therefore, the researchers conducted the initial query, which identified 3,807 patients receiving ICIs with concurrent GLP-1 RAs; after propensity score matching on more than 20 baseline characteristics including demographics, comorbidities, and baseline clinical features, 3,429 matched patients in each cohort were analyzed over a 5-year follow-up period.

Across both the 3-year and 5-year follow-up windows, GLP-1 RA exposure was independently associated with significantly improved overall survival. At 3 years, GLP-1 RA use corresponded to an HR of 0.69 (95% CI, 0.64-0.75; P <.001), with survival probability remaining higher in the GLP-1 RA cohort through the end of follow-up.

The survival advantage was maintained at 5 years, with an HR of 0.71 (95% CI, 0.65-0.76; P <.001). In absolute terms, 5-year all-cause mortality was 32% among GLP-1 RA users (1091 of 3411 patients) compared with 45% among those not receiving GLP-1 RAs (1545 of 3410 patients) — a 13 percentage-point absolute risk reduction.

Of note, no statistically significant survival benefit was observed at the 1-year end point (HR 0.65; 95% CI, 0.59-0.71; log-rank P = .521), suggesting the protective effect may emerge over longer treatment exposure, Jajja explained.

Can the use of GLP-1s help to mitigate adverse events after ICI treatment?

GLP-1 RA use was also associated with a lower burden of immune-related adverse events. For pyrexia, GLP-1 RA users demonstrated a significantly reduced 3-year incidence (risk difference, –2.5%; OR, 0.73; 95% CI, 0.61-0.87), with similar protective trends observed at 5 years.

Neutropenia rates were numerically lower in the GLP-1 RA cohort at both 3 years (5.7% vs 6.5%, respectively; OR, 0.87; 95% CI, 0.71-1.06) and 5 years (OR, 0.84; 95% CI, 0.68-1.02), though these differences did not reach statistical significance.

Across the full 5-year outcomes summary, GLP-1 RA users demonstrated consistently lower rates across additional adverse outcomes: malaise and fatigue (25% vs 29%, respectively), sepsis (15% vs 18%), cachexia (4% vs 5%), and pneumonia (14% vs 18%).

What future directions will be taken with GLP-1 RAs and ICI treatment in cancer?

Jajja and colleagues concluded that, in this large real-world analysis of 177,230 patients receiving ICIs, concurrent GLP-1 RA use was associated with significantly improved long-term survival and a reduced burden of irAEs, including lower rates of pyrexia, neutropenia, sepsis, cachexia, and pneumonia.

GLP-1 RAs, such as semaglutide and liraglutide, are known to carry anti-inflammatory and immune-modulatory properties in preclinical models, and Jajja noted that these findings suggest a potential synergistic or protective effect of GLP-1 RAs in the immunotherapy setting.

To conclude, Jajja noted that important metabolic and treatment-selection confounders may not have been fully captured by electronic medical record-based data. Therefore, the researchers plan to evaluate a prospective investigation to clarify underlying mechanisms and the clinical implications of GLP-1 RA use in patients on checkpoint inhibitors.

Reference

Jajja S, Thukral J, Abdalla A, et al. The association of GLP-1 receptor agonist use with survival and immune-related adverse events in patients receiving immune checkpoint inhibitors: A multi-institutional real-world analysis. J Clin Oncol. 2026;44(suppl 16):11000. doi:10.1200/JCO.2026.44.16_suppl.11000.