Long-term cancer risk in users of GLP-1 agonists in Denmark: a nationwide emulated trial.

BACKGROUND

The long-term cancer safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) in real-world settings remains unclear, with limited long-term clinical and observational studies. We clarify the long-term cancer risk.

METHODS

This register-based nationwide emulated trial includes all Danes initiating treatment with GLP-1RA or dipeptidyl peptidase-4 inhibitors (DPP-4i) 2007-2019, propensity score matched 1:1 on baseline characteristics and followed 10 years. The primary outcome was risk differences for cancer, estimated for long-term sustained use of GLP-1RA vs DPP-4i using g-computation accounting for time-varying patient characteristics. Secondary outcomes included "death without prior cancer" and the composite outcome "death or cancer". Analyses included sex stratified estimates and Cox hazard ratios (HR).

FINDINGS

After 195,702 person-years 4758 developed cancer. Among sustained users of GLP-1RA, 4·1 (95% CI 0·4-7·2) more patients developed cancer per 100, compared to 100 DPP-4i patients 10-years post-initiation (HR: 1·35 [95% CI 1·05-1·73] 6-10 years post-initiation). The excess cancer risk was 6·6 (95% CI 1·8-10·7) per 100 women and 2·2 (95% CI -2·2 to 6·2) per 100 men. Fewer patients "died without prior cancer" in users of GLP-1RA (per 100 users: -4·9 [95% CI -7·6 to -2·4]). There was no difference in risk of "death or cancer" per 100 users: -1·15 (95% CI -4·9 to 2·5).

INTERPRETATION

Long-term sustained users of GLP-1RA had a small increased risk of cancer; potentially explained by a survival benefit. Residual confounding by body mass index cannot be ruled out.

FUNDING

The Scientific Committee of the Danish Cancer Society (R354-A20492-23-S3 to LSM).