Revisiting metformin as a chemotherapy adjuvant: a systematic review and meta-analysis based on recent randomized-controlled trials

Abstract

The primary objective is to assess metformin’s impact on progression free survival (PFS), overall survival (OS), and overall response rates (ORR). Secondary objectives included chemotherapy-related toxicity, glucose metabolism, and quality of life. A systematic review and meta-analysis were conducted following PRISMA guidelines and registered prospectively in PROSPERO. A comprehensive literature search was performed in November 2024 across PubMed, Google Scholar, Ovid MEDLINE, and ClinicalTrials.gov. Randomized controlled trials evaluating metformin as an adjunct to chemotherapy were included. The primary outcomes assessed were PFS, OS, and ORR; secondary outcomes included chemotherapy-related side effects, glucose metabolism, and quality of life. Data extraction and quality assessment were performed using standardized tools, and statistical analyses were conducted using RevMan 5.4 Heterogeneity was assessed using the I² statistic, and a random-effects model was applied when necessary. Nineteen RCTs involving 3,502 participants were included. Subgroup analyses demonstrated a significant OS benefit when metformin (1500 mg/day) was combined with platinum-based chemotherapy (HR = 0.61, 95% CI 0.46–0.81; p  = 0.0006). Metformin also significantly improved ORR in patients with breast cancer (OR = 1.86, 95% CI 1.19–2.92; p  = 0.007) and in studies using a 500 mg/day dose (OR = 3.39, 95% CI 1.37–8.39; p  = 0.008). Overall, metformin significantly improved ORR (OR = 1.59, 95% CI 1.02–2.46; p  = 0.04). However, no significant improvements were observed in overall PFS (HR = 1.08, 95% CI 0.96–1.22; p  = 0.19) or OS (HR = 1.08, 95% CI 0.90–1.30; p  = 0.41). Grade ≥3 adverse events were comparable between groups (OR = 1.10, 95% CI 0.66–1.84; p  = 0.72). Adjunctive metformin did not improve overall or PFS but was associated with a higher ORR, driven by increased complete responses, without increasing high-grade toxicity. A survival benefit was observed in exploratory subgroup analyses at a 1500 mg/day dose in platinum-based chemotherapy, warranting prospective trials to clarify these findings.