Systematic review and meta-analysis of the effect of metformin treatment on overall mortality rates in women with endometrial cancer and type 2 diabetes mellitus

Pérez‐López, Faustino R.; Pasupuleti, Vinay; Gianuzzi, Ximena; Palma-Ardiles, Gabriela; Hernández-Fernández, Wendy; Hernández, Adrian V.

doi:10.1016/j.maturitas.2017.04.001

Cited by 36 publications

(22 citation statements)

References 41 publications

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“…In contrast, the same study found that the use of sulphonylureas or insulin was associated with 1.49‐ (95% CI: 1.00‐2.23) and 2.58‐fold (95% CI: 1.72‐3.90) higher risks of breast cancer death. Other recent meta‐analyses have also reported a beneficial effect of metformin on incidence and/or survival in various cancers including liver, prostate cancer, colorectal cancer, endometrial cancer and pancreatic cancer …”

Section: Resultsmentioning

confidence: 90%

“…53 In contrast, the same study found that the use of sulphonylureas or insulin was associated with 1.49-(95% CI: 1.00-2.23) and 2.58-fold (95% CI: 1.72-3.90) higher risks of breast cancer death. Other recent meta-analyses have also reported a beneficial effect of metformin on incidence and/or survival in various cancers including liver, 54,55 prostate cancer, 56 colorectal cancer, 57,58 endometrial cancer 59,60 and pancreatic cancer. 61 Although some observational studies show clear evidence of survival benefit in cancer patients with diabetes receiving metformin, the situation is by no means clear.…”

Section: Potential Use In Oncologymentioning

confidence: 89%

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Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Shah

Stonier

2018

J Clin Pharm Ther

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Section: Resultsmentioning

confidence: 90%

Section: Potential Use In Oncologymentioning

confidence: 89%

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Shah

Stonier

2018

J Clin Pharm Ther

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“…Epidemiological studies based on EC patients boost this point of view. Metformin treatment is associated with significant reduction in overall mortality irrespective of diabetes status in patients with EC . A meta‐analysis has shown that metformin use was associated with a significant reduction in overall mortality (compared to no metformin; adjusted hazard ratio, 0.64; 95% CI, 0.45–0.89; P = 0.009).…”

Section: A New Strategy Of Fertility‐sparing Treatment Combined With mentioning

confidence: 99%

“…A meta‐analysis has shown that metformin use was associated with a significant reduction in overall mortality (compared to no metformin; adjusted hazard ratio, 0.64; 95% CI, 0.45–0.89; P = 0.009). When evaluation was restricted to patients with EC and type 2 DM, metformin use was associated with a significant reduction in overall mortality (adjusted hazard ratio, 0.50; 95% CI, 0.34–0.74; P = 0.0006) . One study not included in this meta‐analysis – a retrospective review of 351 patients with EC, BMI ≥ 30 kg/m 2 – revealed that metformin use in obese women with type I EC was associated with reduced incidence of cancer recurrence (1.9% of women administered metformin vs 10.3% in women not administered metformin [ P = 0.05]) …”

Section: A New Strategy Of Fertility‐sparing Treatment Combined With mentioning

confidence: 99%

New therapeutic approaches for the fertility‐sparing treatment of endometrial cancer

Mitsuhashi

Shozu

2020

J of Obstet and Gynaecol

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This review seeks to describe new fertility-sparing endometrial cancer (EC) treatment strategies that take into consideration the medical and general health background of patients. We particularly focus on the application of metformin, which is a biguanide widely prescribed for treatment of type 2 diabetes mellitus. Fertilitysparing treatment using progestin is considered a standard treatment option for patients with atypical endometrial hyperplasia (AEH) and EC who desire to conceive. A previous meta-analysis of fertility-sparing treatments revealed a high remission rate; however, high rates of relapse persisted. Most young patients with AEH and EC who are subjected to fertility-sparing treatment have a background of obesity, insulin resistance and abnormal glucose tolerance complicated with polycystic ovary syndrome. Recently, metformin has been attracting more attention in the field of cancer research. Several in vitro and in vivo reports regarding the efficacy of metformin in EC management have accumulated. Thus far, the efficacy of combining metformin with progestin has been revealed in a single phase II study of medroxyprogesterone acetate in combination with metformin as a fertility-sparing treatment for patients with AEH or EC. In addition to improving the metabolic profile of patients with EC having metabolic disorders, metformin supplementation may improve the long-term oncological outcome of these patients. To date, many clinical trials employing progestin and metformin as a fertility-sparing treatment of AEH and EC are ongoing. In the near future, it is expected that the clinical advantage of metformin progestin combination therapy will be clarified.

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“…Recently, metformin, an oral biguanide anti-diabetic drug for type 2 diabetes, was shown to have significant anticancer activity and considered a novel treatment option through drug repositioning (4), including for endometrial cancer (5-7). However, it should be noted that almost all previous studies were conducted with supra-pharmacological concentrations (doses) of metformin, that is, 10–100 times higher than maximally achievable therapeutic concentrations found in patients with type 2 diabetes mellitus (8).…”

Section: Introductionmentioning

confidence: 99%

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

Suh

Lee

Park

et al. 2019

Preprint

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18This study was performed to evaluate the anticancer effects of tolerable doses of metformin 19 with or without medroxyprogesterone (MPA) in endometrial cancer cells. Cell viability, cell 20 invasion, and levels of matrix metallopeptidase (MMP) and transforming growth factor (TGF)-21 β1 were analyzed using three human endometrial adenocarcinoma cell lines (Ishikawa, KLE, 22 and USPC) after treatment with different dose combinations of MPA (0, 10 µM) and metformin 23 (0, 100, 1000 µM). Combining metformin (0, 100, 1000 µM) and 10 µM MPA induced 24 significantly decreased cell viability in a time-and dose-dependent manner in Ishikawa cells, 25 but not in KLE and USPC cells. There was no dose-or time-dependent cell growth inhibition, 26 or positive western blot results for the expression of progesterone receptors and phospho-27 AMPKα, following treatment with any combination of metformin (0, 100, 1000 µM) and 10 28 µM MPA in KLE and USPC cells. In KLE cells, metformin treatment alone significantly 29 inhibited cell invasion in a dose-dependent manner (1.31±0.05, 0.94±0.04, 0.83±0.05 at 0, 100 30 µM, 1000 µM, respectively; p<0.0005). The inhibitory effect of metformin was reversed to 31 create a stimulating effect when metformin was combined with 10 µM MPA (1.10±0.05, 32 1.42±0.18, 1.41±0.26 at 0, 100, 1000 µM, respectively; p<0.005). MMP-9 and TGF-β1 showed 33 similar trends in terms of cell invasion in KLE cells. In conclusion, the anti-invasive effect of 34 metformin in KLE cells was completely reversed to the state of no treatment by the addition of 35 MPA; this might be mediated through MMP-9 and TGF-β1. Our study suggests the possibility 36 of these combinations doing harm, rather than good, under some conditions. 3 37Recently, metformin, an oral biguanide anti-diabetic drug for type 2 diabetes, was 55 shown to have significant anticancer activity and considered a novel treatment option through 56 drug repositioning (4), including for endometrial cancer (5-7). However, it should be noted that 57 almost all previous studies were conducted with supra-pharmacological concentrations (doses) 58 of metformin, that is, 10-100 times higher than maximally achievable therapeutic 59 concentrations found in patients with type 2 diabetes mellitus (8). Such levels exceed the 4 60 maximum dose that could cause lactic acidosis, one of the most serious side effects of 61 metformin. Any anticancer effect of metformin should be studied only in the condition of 62 achievable therapeutic concentrations (8, 9). 63Another approach for the development of novel anticancer drug regimens is the use of 64 drug combinations. Although hormonal therapy is currently recommended only for lower-65 grade endometrioid histology in clinical guidelines, there is evidence suggesting several 66 anticancer mechanisms of progestational agents, which could show significant effects in 67 poorly-differentiated endometrioid adenocarcinoma, as well as USPC (2, 10, 11), particularly 68 when combined with metformin (12). 69The purpose of this study w...

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Systematic review and meta-analysis of the effect of metformin treatment on overall mortality rates in women with endometrial cancer and type 2 diabetes mellitus

Abstract: Metformin treatment is associated with a significant reduction in OM irrespective of diabetes status in patients with EC. The survival benefit suggests that diabetes screening and maintenance of good glycemic control may improve outcomes in EC.

Cited by 36 publications

References 41 publications

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

Repurposing old drugs in oncology: Opportunities with clinical and regulatory challenges ahead

New therapeutic approaches for the fertility‐sparing treatment of endometrial cancer

Medroxyprogesterone reverses tolerable dose metformin-induced inhibition of invasion via matrix metallopeptidase-9 and transforming growth factor-β1 in KLE endometrial cancer cells

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