Gamborg Mads, Grand Mia Klinten, Grell Kathrine, Rosthøj Susanne, Pedersen-Bjergaard Ulrik, Torp-Pedersen Christian, Mørch Lina Steinrud
Cancer and Medicine, Danish Cancer Institute, Danish Cancer Society, Copenhagen, Denmark.
Statistics and Data Analysis, Danish Cancer Institute, Danish Cancer Society, Copenhagen, Denmark.
Lancet Reg Health Eur. 2025 Jun 14;55:101346. doi: 10.1016/j.lanepe.2025.101346. eCollection 2025 Aug.
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.
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).
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).
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.
The Scientific Committee of the Danish Cancer Society (R354-A20492-23-S3 to LSM).
在现实环境中，胰高血糖素样肽-1受体激动剂（GLP-1RAs）的长期癌症安全性仍不明确，长期临床和观察性研究有限。我们阐明了长期癌症风险。
这项基于登记的全国性模拟试验纳入了2007年至2019年开始使用GLP-1RA或二肽基肽酶-4抑制剂（DPP-4i）治疗的所有丹麦人，根据基线特征进行1:1倾向评分匹配，并随访10年。主要结局是癌症的风险差异，使用考虑患者随时间变化特征的g计算法，对长期持续使用GLP-1RA与DPP-4i进行估计。次要结局包括“无癌症病史的死亡”和复合结局“死亡或癌症”。分析包括按性别分层的估计值和Cox风险比（HR）。
在195,702人年的随访期内，4758人患癌症。在GLP-1RA的持续使用者中，每100人中有4.1（95%CI 0.4-7.2）人在开始治疗10年后患癌症，而每100名DPP-4i使用者中为10人（开始治疗6至10年后的HR：1.35[95%CI 1.05-1.73]）。每100名女性的额外癌症风险为6.6（95%CI 1.8-10.7），每100名男性为2.2（95%CI -2.2至6.2）。GLP- 1RA使用者中“无癌症病史的死亡”患者较少（每100名使用者：-4.9[95%CI -7.6至-2.4]）。每100名使用者的“死亡或癌症”风险无差异：-1.15（95%CI -4.9至2.5）。
GLP-1RA的长期持续使用者患癌症的风险略有增加；这可能是由生存获益所解释。不能排除体重指数的残余混杂因素。
丹麦癌症协会科学委员会（授予LSM的R354-A20492-23-S3）。
