Metformin use improves survival in diabetic patients with nonmuscle invasive bladder cancer

Use of metformin leads to improved oncological outcomes in diabetic patients with nonmuscke invasive bladder cancer treated with intravesical Bacille Calmette-Guerin (BCG), according to a Singapore study.

“[O]ur study supported the association of improved disease-specific survival (DSS) and overall survival (OS) in patients with diabetes mellitus on metformin with nonmuscle invasive bladder carcinoma treated with intravesical BCG,” the researchers said.

This study collected and analysed medication use from a prospectively maintained database of 122 patients with nonmuscle invasive bladder cancer treated with intravesical BCG, who were recruited under a randomized controlled trial. DSS and OS were assessed using Kaplan-Meier curves.

Fifty-three patients (43.4 percent) experienced disease recurrence and 21 (17.2 percent) had disease progression over a median follow-up of 102 months (range, 3–357). No significant difference in mortality was seen between patients with and without diabetes mellitus. [Singapore Med J 2020;doi:10.11622/smedj.2020121]

On the other hand, a significant difference in OS was found among patients without diabetes mellitus, patients with diabetes mellitus on metformin, and patients with diabetes mellitus not on metformin (p=0.033). Those on metformin showed the best prognosis. Of note, metformin use resulted in a significantly lower DSS (p=0.042), while other oral hypoglycaemic agents, insulin, or statins did not correlate with disease recurrences or progression.

“One of the proposed mechanisms for the antitumour properties of metformin involves the inhibition of the phosphatidylinositol 3-kinase (PI3k)/protein kinase B (Akt)-mTOR pathway,” the researchers explained. “Recent data suggest that the PI3k-Akt-mTOR signalling pathway plays a central role in controlling bladder cancer cell growth.” [J Cell Biol 2007;178:437-451]

Other studies corroborated this finding, showing that 55 percent of human bladder tumours had increased expression of phosphorylated AKT. In vitro, mTOR inhibition prevented the growth of bladder cancer cells in a dose-dependent manner, and the combination of metformin and other mTOR inhibitors showed a synergistic effect on the inhibition of cell proliferation in other cell lines. [Am J Pathol 2010;176:3062-3072; Clin Cancer Res 2011;17:2863-2873; Anticancer Res 2012;32:1627-1637; J Biol Chem 2014;289:27692-701]

“The antiproliferative actions of metformin are hypothesized to manifest via the inhibition of the activation of AKT1, mTOR, and insulin-like growth factor 1 receptor among other downstream signalling mediators,” the researchers said.

A study by Wang and Wu also presented further evidence regarding the role of metformin in the PI3k-Akt-mTOR pathway. They found that using metformin to treat bladder cancer cell lines T24 and BIU-87 led to reduced cell proliferation and downregulation of phosphorylated-mTOR on Western blot arrays. [Oncol Lett 2015;10:975-981]

A study by Zhang and colleagues showed similar findings of inhibited proliferation and colony formation in the cell lines 5637 and T24 with metformin. In addition, they showed in a xenograft model how daily dosing of metformin inhibited tumour growth. [Int J Mol Sci 2013;14:24603-18]

“Prospective studies with larger patient populations are needed to validate the role of metformin as potential therapy for bladder cancer,” researchers of the current study said.