Metformin use may reduce CRC risk

Metformin treatment in patients with type 2 diabetes (T2D) may have an added benefit – reduction in colorectal cancer (CRC) or colorectal adenoma incidence, a recent meta-analysis suggested.

“[M]etformin use in people with T2D is associated with a lower incidence of benign adenoma and cancer formation, and better oncological outcomes,” said the researchers.

To assess the potential impact of metformin on CRC incidence and outcomes, researchers in Singapore reviewed 58 studies (primarily observational [n=45] with four RCTs) comprising 1,733,229 individuals. The studies compared metformin users vs non-users, metformin users vs non-diabetics, and metformin users vs diabetics on diet management only. Of these, 951,275 individuals were metformin users.

Metformin users had a significantly lower risk of CRC compared with non-users (risk ratio [RR], 0.76, 95 percent confidence interval [CI], 0.69–0.84; p<0.001). [Int J Colorectal Dis 2020;35:1501-1512]

Metformin use also led to a 23 percent lower risk of colorectal adenoma (RR, 0.77, 95 percent CI, 0.67–0.88; p<0.001) and a 39 percent reduced risk of advanced adenoma (RR, 0.61, 95 percent CI, 0.42–0.88; p=0.008) compared with non-use.

Metformin use was also associated with greater overall survival (OS; hazard ratio [HR], 0.60, 95 percent CI, 0.53–0.67) and CRC-specific survival (HR, 0.66, 95 percent CI, 0.59–0.74; p<0.001 for both) compared with non-use.

However, CRC-specific survival did not significantly differ between metformin users vs non-diabetics (HR, 1.01; p=0.969). Cancer recurrence was also reduced in metformin users vs non-users (HR, 0.65; p<0.001), but not vs non-diabetics (HR, 2.1; p=0.369).

Metformin use was associated with improved survival in metastatic CRC vs non-use (HR, 0.77; p<0.001). However, the OS benefit was not noted when compared with non-diabetics (HR, 1.14; p=0.625).

Metformin had no impact on disease-free survival, be it compared with non-use (HR, 0.73; p=0.25), diet management (HR, 0.68; p=0.322), or non-diabetics (HR, 1.13; p=0.425).

According to the researchers, multiple mechanisms could explain the anticancer properties of metformin.

“[M]etformin has been shown to induce apoptosis and autophagy through oxidative stress, inflammation, and metabolic homeostasis via AMPK and mTOR pathways … Metformin also exerts destructive effects on cancer stem cells and may work synergistically with chemotherapy drugs, all of which reduce cancer risk and progression, increasing survival probability,” they said.

Metformin also reduces hyperglycaemia, hyperinsulinemia, and IGF-1 levels, all of which are growth factors in cancer development and progression, they added.

Meta-regression analysis showed that age and aspirin use did not influence the effect of metformin on CRC development. “Aspirin has been shown to reduce incidence of colorectal neoplasia; thus, our results may be interpreted independently of the effects of aspirin,” said the researchers. The association between metformin use and reduced CRC risk appeared greater in current or previous smokers.

The researchers acknowledged possible confounding due to the potential use of other antihyperglycaemic drugs. They also called for research into assessing the impact of glycaemic control and metformin dose and duration on CRC risk.