The association between chronic use of metformin and risk of gastric cancer (GC) has been investigated with contradicting results. We aimed to study the association between chronic use of metformin and GC by using data from the Stomach cancer Pooling (StoP) Project, an epidemiological consortium of case-control studies on GC.
Data from three studies of the StoP Project with available information on metformin intake were analyzed.
Multivariable logistic regression models were used to estimate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between chronic use of metformin and GC risk. Analyses were adjusted for sex, age, socioeconomic status, body mass index, smoking status, alcohol drinking status, and history of diabetes. Study-specific ORs and 95% CIs were then pooled with a random-effects model.
The dose-response relationship between the duration of metformin intake and GC was assessed with a one-stage logistic model, and the duration of intake was modelled using second-order fractional polynomials.
The OR of GC in metformin users versus non-users was 1.01 (95% CI=0.61, 1.67). The association between metformin and GC did not change among different strata of study participants’ characteristics or when restricting the analyses to those with a history of diabetes.
The dose-response analysis showed a slightly reducing trend in the OR of GC and a borderline significant association with increasing duration of metformin intake.
The results of our study do not clearly support an association between chronic use of metformin and GC, warranting further research.
- • In contrast with a number of previous studies, the overall analysis showed no appreciable association between chronic metformin use and gastric cancer.
- • The findings were similar when stratifying according to study participants’ characteristics, as well as to subsite or histological classification of gastric cancer.
- • The association was not significant regardless of participants’ previous history of diabetes.
- • The dose-response analysis, however, suggests that metformin intake might slightly reduce the risk of gastric cancer, though confirmation by further studies is needed.
The use of metformin has been postulated in the etiology, progression, or prognosis of several types of cancer, especially among people that suffer from type 2 diabetes . Most studies investigating gastric cancer (GC) risk reported a protective effect of metformin use , while others did not report any association . In addition, previously published meta-analyses generally showed that metformin use might reduce the risk of GC .
The potential mechanisms underlying the anti-cancer activity of metformin include many potential biochemical pathways. Among them, the hypoxia inducible factor 1α (HIF1α) and glucose metabolism can modify the tumor microenvironment. In fact, the HIF1α can regulate angiogenesis in the tumor as a response to hypoxia . In hypoxic conditions, the PI3k/Akt/HIF1α pathway gets activated and regulates the glucose metabolism of the tumor . Metformin could suppress the growth and progression of GC by inhibiting the HIF1α/PKM2 pathway . Another pathway involved includes the activation of the AMPK and the inhibition of NF-ĸB signaling. By doing so, metformin promotes apoptosis and the interruption of the cell-cycle, and inhibits cell migration and invasion .
Thus, metformin may reduce the risk of GC by inhibiting cell growth, invasion, migration and metastasis. However, to date the association between metformin and GC is unclear, with conflicting results reported by previous studies . Hence, the aim of this study is to evaluate the association between chronic use of metformin and GC by conducting a pooled analysis within the Stomach cancer Pooling (StoP) Project .