Colorectal cancer (CRC) is the third most common cancer in the United States (US) for both men and women [1]. CRC incidence rates are higher for non-Hispanic Black Americans compared to White Americans (41.7 vs. 35.7 cases per 100,000, respectively [2]), and for individuals with lower socioeconomic status (SES), a construct that encompasses education, income, and access to basic healthcare including CRC screening [3]. Type 2 diabetes, characterized by insulin resistance and hyperglycemia, is an emerging risk factor for CRC [4], [5], [6], [7], with epidemiological studies showing approximately 30% higher risk compared to persons without diabetes [6], [7], [8]. Higher diabetes prevalence in the non-Hispanic Black community compared to White individuals (16.8% vs. 11.2%, respectively [9]) may therefore contribute to racial disparities in CRC risk. Given the epidemic of type 2 diabetes in the United States, approaches to mitigate excess risk for CRC among people with diabetes warrant investigation.

Emerging epidemiological evidence indicates that use of the biguanide drug metformin, an oral hypoglycemic agent for type 2 diabetes not adequately controlled by diet or physical activity [10], is associated with lower CRC risk in people with diabetes [11], [12], [13], [14], [15]. A recent meta-analysis including 28 studies and 2.1 million persons with diabetes demonstrated that metformin use was associated with 29% lower risk for incident CRC compared to persons with diabetes not taking metformin [12]. Hyperglycemia and hyperinsulinemia are believed to contribute significantly to the pathophysiology of CRC via activation of anabolic signaling receptors (e.g. the insulin and insulin-like growth factor receptors) and the provision of adenosine tri-phosphate (ATP) required for anabolic processes and cell proliferation [5], [16]. Consequently, the protective effect of metformin may involve systemic metabolic effects including improved glycemic control through inhibition of hepatic gluconeogenesis and improved insulin sensitivity [17]. At the cellular level, metformin inhibits complex I of the mitochondrial electron transport chain leading to cellular accumulation of adenosine monophosphate (AMP) and activation of the energy-sensing AMP-activated protein kinase (AMPK). This promotes activation of autophagy and apoptosis and inhibits cell proliferation [17]. Metformin use is associated with only mild side effects and does not increase risk for hypoglycemia [10], [18]. Consequently, treatment with metformin is a potentially attractive intervention for persons with diabetes and to control hyperglycemia and to mitigate risk for CRC.

There are currently few studies that report associations between metformin and CRC risk in persons with diabetes and lower SES, with even fewer studies including a large number of participants who identify as non-Hispanic Black and low SES. In this report, we describe associations between metformin use and risk for incident CRC in the Southern Community Cohort Study (SCCS), a prospective cohort study of predominantly low SES and non-Hispanic Black Americans from the southeastern United States [19]. We hypothesized that self-reported metformin use would be associated with lower risk for incident CRC in people with diabetes.