GLP-1 receptor agonist vs aspirin for primary prevention of colorectal cancer: Evidence from a real-world head-to-head comparison.

18 Background: Colorectal cancer (CRC) remains a leading cause of cancer-related morbidity and mortality. While aspirin has long been studied and utilized for chemoprevention, emerging evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs) may also confer anticancer benefits by exerting anti-inflammatory and anti-proliferative effects in CRC cell lines through inhibition of the PI3K/Akt/mTOR pathway. Despite this mechanistic promise, comparative effectiveness data is limited. This study presents the first large-scale, real-world, head-to-head comparison of GLP-1RA versus aspirin for primary CRC prevention. Methods: We used de-identified data from TriNetX, which encompasses 150 million patients across 106 health organizations. GLP-1RA users were matched to aspirin users utilizing propensity score matching, which adjusted for demographics, comorbidities, and confounders. The primary endpoint was CRC incidence. The index date was defined as the first documented prescription or administration of either therapy, with follow-up beginning 6 months post-index event. Sensitivity analysis was performed at 12 and 36-months. Median follow-up was 2,153 days for GLP-1RA users and 1,743 days for aspirin users. Patients with outcomes prior to the study window were excluded. Subgroup analysis included age, BMI, diabetes status, tobacco use, atherosclerotic disease, and GLP-1RA type. Multivariate logistic regression assessed associations with results reported as risk ratio (RR) with 95% CI. Results: After matching, 281,656 patients were analyzed (140,828 per cohort), with similar demographics (mean age 58; 69% female; 67% White, 12% Black, 2.3% Asian). CRC incidence was 0.13% (183/140,758) in GLP-1RA users vs 0.176% (247/140,692) in aspirin users, yielding an ARR of 0.0455% and NNT of 2,198. GLP-1RA use was associated with a 26% lower risk of CRC [RR: 0.741 (0.612–0.896)].This benefit was consistent across sensitivity analyses at 12 months [RR: 0.738 (0.605–0.900)] and 36 months [RR: 0.779 (0.620–0.979)], and across subgroups: age 18-44 [RR:0.537 (0.320-0.901)], age 45-64 [RR:0.687 (0.539-0.876)], age ≥ 65 [RR:0.524 (0.362-0.757)], BMI ≤29 [RR:0.520 (0.353-0.765)], BMI ≥ 30 [RR:0.719 (0.575-0.898)], no atherosclerotic disease [RR:0.792 (0.643-0.974)], A1c ≥ 6.5% [RR: 0.400 (0.205-0.780)], A1c ≤ 6.4% [RR: 0.618 (0.494-0.774)]. Semaglutide was the only GLP-1RA agent to show significant benefit [RR: 0.758 (0.580–0.990)]. No significant associations were observed in tobacco users or those with atherosclerotic disease. Conclusions: In this real-world comparison, GLP-1RAs were associated with a 26% relative reduction in CRC incidence compared to aspirin. These results along with the favorable safety profile of GLP-1RAs could underscore a potential public health impact and warrant prospective validation in randomized clinical trials.