Metformin is a widely prescribed medication in the management of type 2 diabetes mellitus, and numerous epidemiological studies have indicated an association between metformin use and a reduced risk of certain cancers in diabetic populations. However, evidence supporting a role for metformin in cancer prevention remains inconclusive. Exploring tumor-preventive strategies may be particularly relevant for inherited cancer syndromes with high tumor penetrance such as pancreatic neuroendocrine tumors (PNETs) associated with multiple endocrine neoplasia type 1 (MEN1). MEN1 is caused by germline pathogenic variants in the tumor suppressor gene MEN1, and mouse models with Men1 gene loss also develop PNETs. To evaluate whether metformin is associated with altered PNET outcomes in MEN1, we performed a retrospective analysis of MEN1 patients with PNETs, incorporating detailed clinical exposure data and complemented this analysis with a preclinical study using pancreatic islet β-cell-specific Men1-knockout mice treated with metformin. In the clinical cohort, metformin exposure varied substantially with respect to timing and duration relative to PNET diagnosis. No statistically significant association between metformin use and overall survival or metastatic disease was detected in this limited cohort. In the mouse model, treatment with 2 mg/mL metformin in drinking water initiated post-weaning did not prevent PNET development, nor did it alter circulating insulin or glucose levels. These findings indicate that, under the dosing and exposure conditions examined, metformin was not associated with measurable tumor-protective or tumor-preventive effects in MEN1-related PNETs. The study highlights important methodological considerations, including exposure timing and statistical power, and supports the need for prospective studies initiating metformin prior to tumor development in genetically predisposed populations.
Kozlov et al. (Wed,) studied this question.