A retrospective cohort study published in JAMA Network Open found glucagon-like peptide-1 (GLP-1) receptor agonists to be associated with lower all-cause mortality than dipeptidyl peptidase-4 (DPP-4) inhibitors, with no significant difference from sodium-glucose cotransporter-2 (SGLT-2) inhibitors, in older patients with cancer and type 2 diabetes. Radwan et al furthermore noted that the survival benefit over DPP-4 inhibitors persisted across several demographic and clinical factors.
“The potential role of GLP-1 receptor agonists in oncology has drawn interest due to their ability to lower glucose, adiposity, insulin resistance, and systemic inflammation—factors associated with cancer progression,” the investigators remarked. “Although GLP-1 receptor agonists have been associated with a lower incidence of some cancers, [prior to this analysis,] their effect on survival remained unclear.”
Study Details
Using Medicare data from 2013 to 2020, the investigators identified individuals who were older than age 66, had type 2 diabetes, and one of nine cancers (thyroid, pancreatic, bladder, colorectal, lung, kidney, breast, endometrial, or prostate), and survived at least 1 year after their cancer diagnosis, and initiated one of the glucose-lowering study drugs (GLP-1 receptor agonist, SGLT-2 inhibitor, or DPP-4 inhibitor).
Baseline covariates included sociodemographic characteristics, comorbidities, and comedications. To reduce confounding, patients who were prescribed GLP-1 receptor agonists were matched 1:1 on propensity score with those receiving SGLT-2 (n = 2,553 pairs; mean age = 73.9 years; 56.0% male; median follow-up = 1.65 years) and DPP-4 (n = 2,564 pairs; mean age = 74.1 years; 53.1% male; median follow-up = 1.73 years) inhibitors.
Key Findings
The risk of mortality did not appear to differ significantly between those receiving GLP-1 receptor agonists and SGLT-2 inhibitors (hazard ratio [HR] = 1.03, 95% confidence interval [CI] = 0.85–1.23). In contrast, GLP-1 receptor agonist vs DPP-4 inhibitor use was found to be associated with a significantly lower risk of mortality (HR = 0.60, 95% CI = 0.51–0.70). To assess the potential for unmeasured confounding, the investigators calculated E-values: 1.21 and 2.73 for GLP-1 receptor agonists vs SGLT-2 and DPP-4 inhibitors, respectively.
Based on subgroup analyses, GLP-1 receptor agonists and SGLT-2 inhibitors did not appear to differ significantly. However, according to the investigators, the survival benefit with GLP-1 receptor agonists over DPP-4 inhibitors remained consistent across age, sex, non-Hispanic White race, and several cancer types (ie, colorectal, lung, and breast).
The investigators concluded, “A recent study found that high intertumoral GLP-1 receptor expression predicts longer survival in some cancers (eg, bladder) but shorter in others (eg, cervical), highlighting the heterogeneity of GLP-1 receptor signaling. While causality cannot be inferred, our study adds novel evidence on the comparative effectiveness of GLP-1 receptor agonists. The observed survival differences may reflect drug class–specific systemic effects. Although both GLP-1 receptor agonists and DPP-4 inhibitors target the incretin pathway, GLP-1 receptor agonists demonstrate greater reductions in hemoglobin A1c levels and body weight, improved β-cell and cardiac function, and lower albuminuria. These effects may reduce cancer progression by mitigating hyperinsulinemia and inflammation, while also lowering overall mortality through broader health improvements.” They added that clinical trials are needed to confirm the role of GLP-1 receptor agonists in cancer survivorship.
Jingchuan Guo, MD, PhD, of the University of Florida College of Pharmacy, Gainesville, is the corresponding author of the JAMA Network Open article.
Disclosure: The study was funded by National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases. For full disclosures of the study authors, visit jamanetwork.com.
