The effect of metformin on biomarkers associated with breast cancer outcomes: a systematic review, meta-analysis, and dose–response of randomized clinical trials

Purpose: Breast cancer is a leading cause of cancer mortality in developed countries. We performed a meta-analysis of randomized clinical trials to investigate the effect of metformin on biomarkers associated with breast cancer outcomes and to explore the dose–response relationship. Methods: A systematic search was performed from onset of the database to January 2019 in MEDLINE/PubMed, SCOPUS, and Cochrane library to identify randomized clinical trials investigating the impact of metformin on insulin, glucose, CRP, leptin, body mass indices (BMI), cholesterol, Ki-67, and Homeostatic Model Assessment for Insulin-Resistance (HOMA-IR). Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence intervals (CI) using a random-effects models. Results: Nine studies providing 1,363 participants were included in the meta-analysis. Pooled results showed a significant reduction in insulin (WMD: − 0.99 U/ml, 95% CI − 1.66, − 0.33), glucose (WMD: − 1.78 ml/dl, 95% CI − 2.96, − 0.60), CRP (WMD: − 0.60 mg/l, 95% CI − 0.88, − 0.33), HOMA-IR (WMD: − 0.45, 95% CI − 0.77, − 0.11), leptin (WMD: − 2.44 ng/ml, 95% CI − 3.28, − 1.61), BMI (WMD: − 0.55 kg/m ² , 95% CI − 1.00, − 0.11), and Ki-67 (WMD: − 4.06, 95% CI − 7.59, − 0.54). Results of the subgroup analyses showed that insulin, glucose, and BMI decreased more significantly when the duration of administering metformin intervention was above 4 weeks. We did not observe non-linear changes in the dose–response relationship between metformin and biomarkers as outcomes. Conclusions: Breast cancer patients receiving metformin as treatment for diabetes showed significant reduction in levels of insulin, fasting glucose, CRP, HOMA, leptin, BMI, and Ki-67.