Impact of metformin on the incidence of human cholangiocarcinoma in diabetic patients: a systematic review and meta-analysis

Abstract

Cholangiocarcinoma (CCA) is the second most common liver cancer. Diabetes is a well-known risk factor; however, treatment with metformin has been reported to be protective for several cancers, but data on CCA are still sparse and heterogeneous. We performed this meta-analysis to investigate the role of metformin as a potential protective factor for CCA. In this systematic review and meta-analysis, we searched PubMed/MEDLINE and EMBASE databases, from the date of inception to November 2022, for studies analyzing CCA rate in patients taking metformin. Twenty-nine articles were initially identified, of which four were eligible and included in our systematic review and meta-analysis, from which we estimated the relative risk (RR). The rate of CCA was lower for diabetic patients taking metformin than diabetic patients without metformin intake when comparing two highest quality studies [RR, 0.38; 95% confidence interval (CI), 0.290–0.508; P < 0.001], and three studies with similar inclusion criteria (RR, 0.34; 95% CI, 0.51–0.35; P < 0.001) without significant statistical heterogeneity among them (I2 = 29.83%, P = 0,2326 and I2 = 35.08%; P = 0.2143, respectively). Our study demonstrated a significant impact of metformin in reducing the risk of CCA by nearly 62–66% in diabetic patients taking metformin.

Any Role for Microbiota in Cholangiocarcinoma? A Comprehensive Review

“…In addition, a Chinese and, later, a British meta-analysis confirmed an increased independent risk of iCCA and eCCA in patients with type 2 DM (eCCA OR 1.5; iCCA OR 1.73, respectively) [4,42]. A possible protective role of metformin in the development of CCA has been suggested [37,43], even if further prospective studies are needed.…”

“…Insulin-resistant patients have a higher overall cancer risk due to the mitogenic effect of insulin, which enhances a signaling pathway that activates the transcription of molecules involved in the cell cycle and proliferation [37]. Insulin-resistant patients have a higher overall cancer risk due to the mitogenic effect of insulin, which enhances a signaling pathway that activates the transcription of molecules involved in the cell cycle and proliferation [38,39].…”

Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR Signaling Pathways

“…Various studies showed that the MET is not only capable of decreasing the risk of cancer in patients suffering from diabetes but could also prevent and treat non-diabetic patients suffering from pancreatic, bladder, lung, breast, thyroid, and prostate cancers [10][11][12][13].Besides, MET showed promising results in averting colorectal cancer, squamous cell carcinoma, oral ductal carcinoma in situ , human cholangiocarcinoma, and endometrial cancer [14][15][16][17][18]. Research demonstrates that MET exerts its anticancer effects by activating AMPK, disrupting the crosstalk between the insulin receptor and the G protein-coupled receptor signalling system [19,20].…”

Effects of metformin on cancers in experimental and clinical studies: Focusing on autophagy and AMPK/mTOR signaling pathways

“…[15][16][17][18] Besides, MET showed promising results in averting colorectal cancer, squamous cell carcinoma, oral ductal carcinoma in situ, human cholangiocarcinoma, and endometrial cancer. [19][20][21][22][23] Research demonstrates that MET exerts its anticancer effects by activating AMPK, disrupting the crosstalk between the insulin receptor and the G protein-coupled receptor signalling system. 24,25 Also, the direct insulin-independent action of MET by the AMPK activation leads to downregulating of the mammalian target of rapamycin (mTOR) signalling and protein synthesis in tumour cells.…”

“…Various studies showed that the MET is not only capable of decreasing the risk of cancer in patients suffering from diabetes but could also prevent and treat nondiabetic patients suffering from pancreatic, bladder, lung, breast, thyroid, and prostate cancers 15–18 . Besides, MET showed promising results in averting colorectal cancer, squamous cell carcinoma, oral ductal carcinoma in situ, human cholangiocarcinoma, and endometrial cancer 19–23 . Research demonstrates that MET exerts its anticancer effects by activating AMPK, disrupting the crosstalk between the insulin receptor and the G protein‐coupled receptor signalling system 24,25 .…”