Colorectal cancer (CRC) is the third leading cause of cancer-related deaths worldwide,¹ and its prevalence and mortality rates continue to increase in Korea.² CRC mostly develops from colonic adenomas.³ To reduce the incidence of CRC, the focus has shifted from removal of early-detected adenomas to prevention of the formation of adenomas causing CRC; recent studies have investigated the effects of dietary fiber, calcium, nonsteroidal anti-inflammatory drugs, aspirin, statins, and other medications in the prevention of CRC.^4,5 Since CRC is a cancer associated with lifestyle-related diseases such as diabetes mellitus (DM) or obesity, the therapeutic agents used for these diseases have been investigated for the prevention of CRC.^6,7 Type 2 DM is a known risk factor for CRC worldwide;⁸ hyperinsulinemia caused by insulin resistance influences the incidence of CRC.^9,10,11 Metformin is a biguanide derivative that inhibits gluconeogenesis and glycogen decomposition, and increases glucose absorption in muscle tissues. Unlike other oral hypoglycemic agents, metformin does not cause hypoglycemia; therefore, it is appropriate for the initial treatment of diabetes.¹² Metformin also activates liver kinase B1-dependent AMP-activated protein kinase (AMPK) in the liver, and activated AMPK inhibits the proliferation and growth of cells by inhibiting mammalian target of rapamycin.¹³ A recent study suggests that AMPK activated by low-dose metformin inhibits the formation of aberrant crypt foci (ACF), a surrogate marker of CRC.^14,15 Moreover, it has also been recently reported that the risk of cancers, including CRC, is lower in type 2 DM patients being treated with metformin than those not treated with metformin.^{9,16,17,18,19,20} Some animal studies have revealed that metformin prevents the proliferation of colonic epithelial cells.^21,22 However, it remains to be proven whether the intake of metformin inhibits the occurrence of adenomas, which are the precursor lesions of CRC. In this study, we aimed to investigate if administrating metformin prevented the formation of colonic polyps, particularly adenomas, in patients with type 2 DM.

A number of studies have shown that DM is associated with an increased incidence of CRC, breast cancer, endometrial cancer, renal cancer, liver cancer, and other cancers;²⁵ meta-analyses have proven that the relative risk of CRC is higher in patients with DM.²⁶ Insulin-like growth factor-1 (IGF-1) level increases due to hyperinsulinemia resulting from insulin resistance in DM patients, and elevated IGF-1 levels affect the incidence of colonic adenomas and CRC inducing proliferation and dysplasia of normal and carcinoma cells.²⁷ The incidence and mortality rates of CRC are showing a continuously increasing trend worldwide.² Along with the removal of early-detected CRC or colonic adenomas, the use of preventive medicines is anticipated to be effective in preventing CRC. The most common cause of CRC is development from colonic adenomas after a series of genetic variations. Although the association of DM with colonic adenomas has been verified,^28,29 and metformin has been proven to lower the risk of CRC in patients with type 2 DM,³⁰ results of different studies that have investigated whether metformin decreases the incidence of colonic polyps or adenomas are inconsistent. A Korean study showed that metformin reduced the incidence of colonic adenomas in patients with a history of CRC.³¹ For these reasons, this study compared the detection rate of colonic polyps and adenomas in 3,105 patients with type 2 DM aged ≥40 years with no history of CRC and who were undergoing colonoscopy for the first time by dividing them into two groups: a metformin and non-metformin group. The detection rates of both polyps and adenomas were found to be significantly lower in the metformin group than in the non-metformin group, implying that metformin prevents the incidence of colonic polyps and the occurrence of colonic adenomas, which are precursor lesions of CRC. Although no difference was found in the histologic classification and grade of colonic adenomas between the two groups, the incidence of three colonic adenomas was significantly lower in the metformin group than in the non-metformin group. According to the multivariate analysis performed to identify factors that affect the detection rate of colonic adenomas, age, sex, BMI, TG, HbA1c, smoking status, and DM duration were not found to be associated with the incidence of colonic adenomas. Unlike previous studies that suggested that the use of aspirin and statins was related with the occurrence of colonic adenomas,^32,33 the risk of colonic adenomas was not reduced in patients treated with aspirin or statins in this study. In contrast, metformin use decreased the risk of colonic adenoma incidence by 37%. Therefore, metformin may be effective in preventing the development of colonic adenomas in patients with type 2 DM. This study has a few limitations. It was a single-center retrospective study. Since the study mainly relied on medical records without evaluating the clinical characteristics of patients or the use of aspirin or statins, the duration of medication use was indeterminable. Therefore, the outcome of this study cannot be compared with that of previous studies. Furthermore, the skill-level of physicians who performed colonoscopy for polyp detection was not standardized, and colon cleanliness and colonoscopy withdrawal time were not evaluated as variables that may have affected the detection rate. Unlike previous studies, this study identified the effectiveness of metformin in lowering the occurrence of colonic adenomas in patients with type 2 DM by comparing the detection rates of polyps and adenomas in a large number of subjects with type 2 DM stratified according to metformin use. Large-scale, prospective, randomized studies with various controlled confounding variables will be needed to overcome the study limitations and clearly prove the efficacy of metformin in preventing colonic adenomas.