In post-operative colorectal cancer patients with diabetic mellitus, continuous use of metformin was associated with a significant survival benefit and a further reduction in liver metastases, implying a potential anti-tumorigenic effect of metformin.
In general, people with diabetes have been associated with inferior survival outcomes and are also at increased risk of developing colorectal cancer [16–18]. This public health concern has been raised globally in response to the high prevalence of type II diabetes mellitus in patients with colorectal carcinoma, while the prognosis of patients with colorectal carcinoma is also significantly affected by their high blood sugar levels [19–22]. The risk of colorectal carcinoma for people with diabetes mellitus has been mentioned in some emerging researches, which suggest that diabetic patients with inadequate glycemic control may be at an even higher risk of colorectal carcinoma and often receive polytherapy . Hyperinsulinemia, hyperglycemia and chronic inflammation may cause a higher risk of colorectal cancer [24–27]. Patients with diabetic colorectal cancer have been shown to have shorter overall survival [7, 17, 26].
Metformin is the most extensively prescribed first-line orally administered drug for type II diabetes mellitus [13, 28]. With the amount of metformin use nearly doubling over the past ten years, single-ingredient metformin has been prescribed as non-insulin anti-diabetic treatment for approximately one in every two patients . The American Diabetes Association indicated that metformin monotherapy would be the most appropriate therapy in the initial stage of the disease.
Some studies on antidiabetic medication for alleviating cancer have been conducted due to the fact that hyperinsulinemia, associated with metabolic syndromes or type II diabetes mellitus, is linked to increased colorectal cancer risk . The potential anticancer effects of metformin derive from its multiple activities, and thus the reduced cancer occurrence and death rate in diabetic patients, as well as in patients with colorectal cancer, have been linked to the use of metformin . The chemoprevention properties delivered by metformin inhibit the transformative and hyperproliferative processes that trigger cancer-causing events . Even though research on the molecular mechanisms by which metformin influences numerous cancers is still lacking, suppression of mechanistic target of rapamycin (mTOR) signaling by triggering ataxia telangiectasia mutated (ATM) and liver kinase B1(LKB1) and then adenosine monophosphate-activated protein kinase (AMPK)-dependent and AMPK-independent pathways, along with energy metabolism aberration, cell cycle arrest, and apoptosis or autophagy induction, have appeared as key inhibitors in these processes to prevent protein synthesis and cells from growing . Metformin is able to trigger p53 by activating AMPK and hence eventually put a stop to the cell cycle. Therefore, in consideration of metformin’s prospects on cancer treatment, metformin cannot only be applied in radiotherapy and chemotherapy but also be utilized to prevent many types of cancers . There is a hypothesis about synergistic or additive inhibitory effect of metformin with acetylsalicylic acid (ASA, aspirin) which a drug prescribed for cardioprotection of patient with or without diabetes mellitus II and also inhibit the mTOR signalling pathway. However, randomized controlled trials are required to verify this hypothesis .
The use of metformin can reduce the risk and mortality of cancer among diabetic patients. Evans et al indicated that cancer incidence for patients who received metformin was lower than those without metformin. Recent studies also revealed that the risk of rectal cancer decreased, even with a small amount of metformin, which prevents the growth of cancer cells and reduces their expansion. Recurrence-free survival and cancer specific survival indicators also improved through metformin treatment in patients with colorectal cancer . According to Hosono et al a similar effect was also found in the proliferation of cancer cells in colon cancer, as small doses of metformin (250 mg/day) were associated with the destruction of aberrant crypt foci (ACE), which is an indicator related to the presence of colon cancer . High-doses of metformin were shown to reduce mortality in patients with colorectal cancer . In addition, according to Garrett’s results, the mortality of patients with colorectal cancer, ranging from grade one to four, was reduced by 40% due to the use of metformin . Studies have shown that there is no association between diabetes or metformin treatment and recurrence-free or disease-free survival after surgery for colorectal cancer . In difference our results, it is speculated that differences in race may cause such results. In this study, the statistics also echoed the above-mentioned effects, in which the continuous use of metformin proved to reduce the risk of colorectal cancer in operable patients. Furthermore, the use of metformin was shown to be beneficial for the patients in terms of overall 5-year survival. More importantly, the continuous use of metformin also showed benefits for decreasing liver metastases, which has never been discussed in existing published literature.
The effectiveness of metformin in cancer treatment may be affected by four non-identical factors, namely hypoxic cancer cells, the number of cancer stem cells, cell's inherent sensitivity and the rate of cancer cells’ growth and spreading (36). Metformin can be applied as a complementary therapeutic medium to cure cancer as it is able to lower the probability of cancer occurrence, decrease the mortality rate caused by cancers, enhance the reaction to therapy in cancer cells during radiotherapy and chemotherapy, alleviate tumor activity and malignity, decrease the possibility of recurrence and lower the detrimental impacts caused by androgen deprivation therapy. Furthermore, metformin can be used to prevent cancers and improve the therapies of cancers and non-malignant tumors. However, more comprehensive research and investigation on metformin’s antitumor effects on patients without diabetes is required; and further detailed information on various cells and radiotherapy is needed from the aspects of biology and genetics .
However, a few constraints in this study should be disclosed. Firstly, the NHI database does not provide access to some recognized potentially key clinical covariates, including diet type, smoking, and alcohol use. Secondly, timewise biases were unavoidable as is the case with many experimental researches on this topic .