Background/Objectives:Metformin is one of the most frequently used concomitant medications among prostate cancer (PCa) patients. However, the effects of metformin on all-cause and PCa-specific mortality among men diagnosed with advanced/metastatic PCa treated with androgen-deprivation therapy (ADT) remain poorly understood, but they may be specifically explained by emulating a target trial.Methods:We emulated a target trial of metformin therapy and survival using observational data on 7361 patients diagnosed with advanced PCa, who were treated with ADT, from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2008–2019), with completed follow-up until 2020. We included patients with diabetes, and participants were assigned as either “initiator of metformin within 6 months after advanced PCa diagnosis” or “non-initiator of metformin.” We estimated mortality risks using Cox proportional hazards models with adjustment for risk factors via inverse probability weighting using both intention-to-treat and per-protocol analyses.Results:Over 13 years of follow-up, with a maximum 3 years of follow-up after PCa diagnosis, all-cause mortality occurred in 52 metformin initiators (47.7%) versus 3052 non-initiators (42.1%), while PCa-specific mortality occurred in 36 initiators (33.0%) versus 1919 non-initiators (26.5%). In the intention-to-treat analysis, metformin initiation was not associated with all-cause mortality (Hazard Ratio [HR] = 1.38, 95% CI: 0.98–1.95) or PCa-specific mortality (HR = 0.99, 95% CI: 0.63–1.55). Similarly, in per-protocol analysis, there was no evidence of risk reduction with all-cause (HR = 1.20, 95% CI = 0.80–1.81) or PCa-specific mortality (HR = 1.45, 95% CI = 0.88–2.38) after adjusting for time-varying covariates and allowing a 30-day gap for metformin discontinuation, adjusted for via inverse probability weighting.Conclusions:Our findings align with prior randomized trials showing no survival benefit of metformin in advanced PCa patients receiving ADT. Timing of metformin discontinuation also showed no significant effect. However, the small size of the metformin initiator group precluded subgroup analyses for hormone-sensitive (HSPC) and castrate-resistant prostate cancer (CRPC), limiting our ability to explore potential differential effects.
背景/目的：二甲双胍是前列腺癌（PCa）患者中最常使用的合并用药之一。然而，对于接受雄激素剥夺疗法（ADT）治疗的晚期/转移性前列腺癌患者，二甲双胍对全因死亡率和前列腺癌特异性死亡率的影响尚不明确，但可通过模拟目标试验进行具体探究。 方法：我们利用美国监测、流行病学和最终结果（SEER）-Medicare数据库（2008–2019年）中7361例诊断为晚期前列腺癌并接受ADT治疗的患者观察性数据，模拟了一项关于二甲双胍治疗与生存的目标试验，随访持续至2020年。研究纳入糖尿病患者，参与者被分为“晚期前列腺癌诊断后6个月内启用二甲双胍”组或“未启用二甲双胍”组。我们采用Cox比例风险模型，通过逆概率加权调整风险因素，并分别基于意向性治疗和符合方案集分析评估死亡风险。 结果：在最长13年（前列腺癌诊断后最长3年）的随访期间，二甲双胍启用组109例患者中有52例（47.7%）发生全因死亡，未启用组7252例患者中有3052例（42.1%）发生全因死亡；二甲双胍启用组有36例（33.0%）发生前列腺癌特异性死亡，未启用组有1919例（26.5%）发生前列腺癌特异性死亡。在意向性治疗分析中，启用二甲双胍与全因死亡率（风险比[HR] = 1.38，95% CI：0.98–1.95）或前列腺癌特异性死亡率（HR = 0.99，95% CI：0.63–1.55）均无显著关联。同样，在符合方案集分析中，调整时变协变量并允许30天的二甲双胍停药间隔（通过逆概率加权调整）后，未发现启用二甲双胍能降低全因死亡率（HR = 1.20，95% CI = 0.80–1.81）或前列腺癌特异性死亡率（HR = 1.45，95% CI = 0.88–2.38）的证据。 结论：本研究结果与既往随机试验一致，表明二甲双胍对接受ADT治疗的晚期前列腺癌患者无生存获益。二甲双胍停药时机也未显示显著影响。然而，由于二甲双胍启用组样本量较小，未能进行激素敏感性前列腺癌（HSPC）和去势抵抗性前列腺癌（CRPC）的亚组分析，限制了我们探索潜在差异效应的能力。
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