Spotlight on GLP-1s and cancer

Several recent articles looked at the potential effect of glucagon-like peptide-1 (GLP-1) receptor agonists on cancer risk.

A systematic review and meta-analysis, published by Annals of Internal Medicine on Nov. 9, included 48 randomized controlled trials of GLP-1 receptor agonists that reported rates of obesity-related cancers. It found that GLP-1 receptor agonists probably have little or no effect on risk for thyroid cancer (odds ratio [OR], 1.37; 95% CI, 0.82 to 2.31), pancreatic cancer (OR, 0.84; 95% CI, 0.53 to 1.35), breast cancer (OR, 0.95; 95% CI, 0.60 to 1.49), or kidney cancer (OR, 1.12; 95% CI, 0.78 to 1.60) and may have little or no effect on colorectal, esophageal, liver, gallbladder, ovarian, or endometrial cancer; multiple myeloma; and meningioma. The drugs' effect on gastric cancer is very uncertain, according to the review. Limitations include that the trials were not designed to evaluate cancer outcomes, the review authors said. The findings differ slightly from previous observational studies finding a reduction in obesity-related cancers with GLP-1 receptor agonists, which could be explained by longer follow-up or higher risk of confounding in observational studies. The authors called for longer-term studies with cancer-specific end points.

One such observational analysis of GLP-1 receptor agonists and cancer was published by Diabetes, Obesity & Metabolism on Nov. 3. It used a database to retrospectively compare cancer rates in more than 1 million type 2 diabetes patients who took either metformin or a GLP-1 receptor agonist, both medications, or a dipeptidyl peptidase-4 (DPP-4) inhibitor. Taking metformin or a GLP-1 receptor agonist was associated with lower risk of cancer (hazard ratios [HRs], 0.96 [95% CI, 0.92 to 0.99] and 0.86 [95% CI, 0.82 to 0.89], respectively, vs. a DPP-4 inhibitor). Dual therapy was associated with an even greater reduction (HR, 0.61 [95% CI, 0.57 to 0.65]). The association was more pronounced in younger, male patients with obesity than in other groups. The apparently synergistic effects of metformin and a GLP-1 receptor agonist are a novel finding of this study, according to its authors. “These associations should be interpreted as hypothesis-generating, and, considering the observational nature of our study, causality cannot be inferred,” they cautioned.

Another retrospective analysis, based on a Florida database, was published by JAMA Oncology on Aug. 21. It used a target trial emulation design to assess incidence of 14 cancer types in 43,317 patients who took GLP-1 receptor agonists and 43,315 matched patients who did not. Overall incidence rates of the studied cancers were 13.6 per 1,000 person-years in the GLP-1 cohort, compared to 16.4 per 1,000 in the matched patients (hazard ratio [HR], 0.83 [95% CI, 0.76 to 0.91]; P=0.002). The largest risk reductions were seen in endometrial cancer (HR, 0.75 [95% CI, 0.57 to 0.99]; P=0.05), ovarian cancer (HR, 0.53 [95% CI, 0.29 to 0.96]; P=0.04), and meningioma (HR, 0.69 [95% CI, 0.48 to 0.97]; P=0.05). GLP-1 receptor agonists were associated with nonsignificant increase in risk of kidney cancer (HR, 1.38 [95% CI, 0.99 to 1.93]; P=0.04). The study authors called for “longer-term follow-up to clarify the underlying mechanisms and clinical implications of these findings.”

The “multifaceted and complex” relationship between diabetes and cancer was discussed in an editorial published by The Lancet Diabetes & Endocrinology on Nov. 26. It summarized recent research on the subject, including the JAMA Oncology study and recent large observational studies of GLP-1 receptor agonists in patients with preexisting cancer diagnoses that have reported significantly lower risk of five-year and all-cause mortality. The editorial also highlighted the “profound emotional toll” of having both diabetes and cancer. “Health systems must be equipped to support patients medically, emotionally, and logistically, recognizing that multimorbidity is now a common reality,” the editorial concluded.