Introduction: Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are becoming more popular in managing type 2 diabetes mellitus (T2DM). Concerns linger over potential links to malignancies like pancreatic and thyroid cancers, requiring more research to clarify their safety profiles. Additionally, evidence suggests GLP-1 RAs may lower colorectal and pancreatic cancer risk, especially in obese and overweight individuals, indicating a protective effect beyond weight loss. Current studies leave a gap in comprehensively understanding cancer risks associated with GLP-1 RAs, which prompts further research to enhance our understanding of their overall safety. Methods: We queried the US Collaborative Network (63 health care organizations) of the TriNetX research database. Patients with T2DM were identified and divided into two cohorts: patients on GLP-1 RAs and patients not on GLP-1 RAs. We excluded tobacco use and alcohol use disorders, obese patients with a body mass index (BMI) of >25 kg/m2, and those with a family history of gastrointestinal malignancy, infectious mononucleosis, chronic gastritis, pernicious anemia, helicobacter pylori infection, or gastroesophageal reflux disease (GERD). We used a 1:1 propensity score matching (PSM) model using patients’ baseline characteristics, medications, labs, and genetics. We compared the rate of gastric cancer and esophageal cancer at the seven-year mark. Results: A total of 2,748,431 patients with T2DM were identified. Of those, 6% (n= 167,077) were on a GLP-1 RA and 94% (n= 2,581,354) were not on a GLP-1 RA. After PSM, both cohorts included 146,277 patients. Patients with T2DM who were on a GLP-1 RA, compared to those who were not, had a statistically significant lower risk of both gastric cancer (0.05% vs. 0.13%,p< 0.0001) and esophageal cancer (0.04% vs. 0.13%,p< 0.0001) at the seven-year mark. Conclusion: The use of GLP-1 RAs in patients with T2DM does not significantly increase the risk of gastric or esophageal cancer. This finding supports the continued use of GLP-1 analogues as a therapeutic option in managing T2DM, considering their well-established benefits and low risk of complications. Based on the study results, these medications may even have a protective effect against these malignancies.
引言：胰高血糖素样肽-1受体激动剂（GLP-1 RAs）在2型糖尿病（T2DM）治疗中的应用日益广泛。关于其可能增加胰腺癌和甲状腺癌等恶性肿瘤风险的担忧持续存在，需要更多研究来明确其安全性特征。此外，有证据表明GLP-1 RAs可能降低结直肠癌和胰腺癌风险，特别是在肥胖和超重人群中，这提示其保护作用可能超越单纯的减重效果。现有研究对GLP-1 RAs相关癌症风险的综合理解仍存在空白，亟需进一步研究以深化对其整体安全性的认识。 方法：我们检索了TriNetX研究数据库中的美国协作网络（涵盖63个医疗机构）。识别T2DM患者并将其分为两组：使用GLP-1 RAs的患者与未使用GLP-1 RAs的患者。我们排除了有烟草使用史、酒精使用障碍、体重指数（BMI）>25 kg/m²的肥胖患者，以及有胃肠道恶性肿瘤家族史、传染性单核细胞增多症、慢性胃炎、恶性贫血、幽门螺杆菌感染或胃食管反流病（GERD）的患者。采用1:1倾向评分匹配（PSM）模型，依据患者基线特征、用药情况、实验室指标和遗传数据进行匹配。比较两组患者在七年观察期内胃癌和食管癌的发生率。 结果：共识别2,748,431例T2DM患者。其中6%（n=167,077）使用GLP-1 RAs，94%（n=2,581,354）未使用。经PSM匹配后，两组各纳入146,277例患者。在七年观察期内，与未使用GLP-1 RAs的T2DM患者相比，使用GLP-1 RAs的患者胃癌（0.05% vs. 0.13%，p<0.0001）和食管癌（0.04% vs. 0.13%，p<0.0001）风险均显著降低，差异具有统计学意义。 结论：T2DM患者使用GLP-1 RAs不会显著增加胃癌或食管癌风险。考虑到GLP-1类似物明确的临床获益和较低的并发症风险，这一发现支持其继续作为T2DM管理的治疗选择。根据研究结果，这类药物甚至可能对上述恶性肿瘤具有保护作用。
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