胰高血糖素样肽-1 受体激动剂与癌症风险的关联——来自药物靶点 Mendelian randomization 和临床试验的证据。
Association of glucagon-like peptide-1 receptor agonists with risk of cancers-evidence from a drug target Mendelian randomization and clinical trials.
机构信息
Department of Plastic and Cosmetic Surgery, Xiangya Hospital, Central South University.
National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan.
出版信息
Int J Surg. 2024 Aug 1;110(8):4688-4694. doi: 10.1097/JS9.0000000000001514.
BACKGROUND
Glucagon-like peptide-1 receptor (GLP1R) agonists have been approved by Food and Drug Administration for management of obesity. However, the causal relationship of GLP1R agonists (GLP1RA) with cancers still unclear.
METHODS
The available cis-eQTLs for drugs target genes (GLP1R) were used as proxies for exposure to GLP1RA. Mendelian randomizations (MR) were performed to reveal the association of genetically-proxied GLP1RA with 14 common types cancer from large-scale consortia. Type 2 diabetes was used as positive control, and the GWASs data including 80 154 cases and 853 816 controls. Replicating the findings in the FinnGen study and then pooled with meta-analysis. Finally, all the related randomized controlled trails (RCTs) on GLP1RA were systematically searched from PubMed, Embase, and the Cochrane Library to comprehensively synthesize the evidence to validate any possible association with cancers.
RESULT
A total of 22 significant cis-eQTL single-nucleotide polymorphisms were included as genetic instrument. The association of genetically-proxied GLP1RA with significantly decreased type 2 diabetes risk [OR (95%)=0.82 (0.79-0.86), P <0.001], which ensuring the effectiveness of identified genetic instruments. The authors found favorable evidence to support the association of GLP1RA with reduced breast cancer and basal cell carcinoma risk [0.92 (0.88-0.96), P <0.001, 0.92 (0.85-0.99), P =0.029, respectively], and with increased colorectal cancer risk [1.12 (1.07-1.18), P <0.001]. In addition, there was no suggestive evidence to support the association of GLP1RA with ovarian cancer [0.99 (0.90-1.09), P =0.827], lung cancer [1.01 (0.93-1.10), P =0760], and thyroid cancer [0.83 (0.63-1.10), P =0.187]. Our findings were consistent with the meta-analysis. Finally, 80 RCTs were included in the systematic review, with a low incidence of different kinds of cancer.
CONCLUSIONS
Our study suggests that GLP1RA may decrease the risk of breast cancer and basal cell carcinoma, but increase the risk of colorectal cancer. However, according to the systematic review of RCTs, the incidence of cancer in patients treated with GLP1RA is low. Larger sample sizes of RCTs with long-term follow-up are necessary to establish the incidence of cancers and evaluate the risk-benefit ratios.
背景
胰高血糖素样肽-1 受体（GLP1R）激动剂已被美国食品和药物管理局批准用于肥胖症的治疗。然而，GLP1R 激动剂（GLP1RA）与癌症之间的因果关系仍不清楚。
方法
利用药物靶点基因（GLP1R）的可用顺式表达数量性状基因座（cis-eQTL）作为 GLP1RA 暴露的替代物。采用孟德尔随机化（MR）方法，从大型联盟中揭示了遗传上确定的 GLP1RA 与 14 种常见类型癌症之间的关联。2 型糖尿病被用作阳性对照，使用包括 80454 例病例和 853816 例对照的 GWAS 数据。在 FinnGen 研究中对结果进行复制，然后进行荟萃分析。最后，从 PubMed、Embase 和 Cochrane Library 中系统地搜索了所有关于 GLP1RA 的相关随机对照试验（RCT），以全面综合证据，验证与癌症相关的任何可能关联。
结果
共纳入 22 个显著的顺式 eQTL 单核苷酸多态性作为遗传工具。遗传上确定的 GLP1RA 与 2 型糖尿病风险显著降低相关[比值比（95%CI）=0.82（0.79-0.86），P<0.001]，这确保了所识别的遗传工具的有效性。作者发现了有利的证据支持 GLP1RA 与乳腺癌和基底细胞癌风险降低[0.92（0.88-0.96），P<0.001，0.92（0.85-0.99），P=0.029]，以及结直肠癌风险增加[1.12（1.07-1.18），P<0.001]相关。此外，没有提示性证据支持 GLP1RA 与卵巢癌[0.99（0.90-1.09），P=0.827]、肺癌[1.01（0.93-1.10），P=0760]和甲状腺癌[0.83（0.63-1.10），P=0.187]之间存在关联。我们的研究结果与荟萃分析一致。最后，系统综述纳入了 80 项 RCT，不同类型癌症的发病率较低。
结论
我们的研究表明，GLP1RA 可能降低乳腺癌和基底细胞癌的风险，但增加结直肠癌的风险。然而，根据对 RCT 的系统评价，接受 GLP1RA 治疗的患者癌症发病率较低。需要更大规模的 RCT 并进行长期随访，以确定癌症的发病率，并评估风险效益比。
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