Association of metformin use with metabolic trajectories and disease progression in prostate cancer patients receiving androgen deprivation therapy: a target trial emulation study

Background Androgen deprivation therapy (ADT) is associated with substantial metabolic deterioration in patients with prostate cancer. Metformin may attenuate ADT-related metabolic complications, although its association with longitudinal metabolic trajectories and prostate cancer outcomes remains uncertain. Methods We conducted a retrospective cohort study emulating a target trial using a 90-day landmark design. Patients with prostate adenocarcinoma initiating ADT between 2015 and 2020 were classified according to metformin exposure during the landmark window (T₀ = Day 90 after ADT initiation). Metformin users initiated and maintained metformin treatment for at least 90 days, whereas controls had no metformin exposure. IPTW was applied to balance baseline characteristics. Longitudinal metabolic outcomes were assessed using weighted linear mixed-effects models, and progression outcomes were analyzed using weighted Cox models. Results Among 823 screened patients, 342 were included in the final analysis (171 metformin users and 171 controls). After IPTW adjustment, baseline covariates were well balanced. Compared with controls, metformin exposure was associated with smaller increases in HbA1c (adjusted difference − 0.34%, 95% CI − 0.58 to − 0.10) and triglycerides (− 26 mg/dL, 95% CI − 46 to − 6) during follow-up. Metformin exposure was also associated with lower observed risks of PSA progression (HR 0.71, 95% CI 0.52–0.96) and CRPC progression (HR 0.67, 95% CI 0.47–0.95), although these findings were considered exploratory because of limited event numbers. Conclusion Metformin exposure was associated with less ADT-related metabolic deterioration and lower observed progression rates. These findings do not establish an anticancer effect and require confirmation in randomized studies.