Highlights
- •We performed the first meta-analysis to examine the effect of metformin on mortality in endometrial cancer.
- •Metformin use is associated with a significant reduction in overall mortality.
- •The findings suggest that good glycemic control may improve survival in endometrial cancer.
- •Larger observational studies are needed to confirm this finding.
Abstract
Background
Obesity, insulin resistance and type 2 diabetes mellitus (T2DM) have been associated
with endometrial cancer (EC). In this systematic review and meta-analysis we evaluated
the effect of metformin on clinical outcomes in patients with EC and insulin resistance
or T2DM.
Methods
Four research databases were searched for original articles published in all languages
up to 30 October 2016. Outcomes of interest were overall mortality (OM), cancer-specific
mortality, disease progression, and metastases. We performed a random effect meta-analysis
of adjusted effects expressed as hazard ratios (HR); heterogeneity among studies was
described with the I2 statistic.
Results
Of the 290 retrieved citations, 6 retrospective cohort studies in women with EC (n = 4723) met the inclusion criteria, and 8.9% to 23.8% were treated with metformin; OM
data was available from 5 studies. In 4 studies of EC patients (n = 4132), metformin use was associated with a significant reduction in OM in comparison
with not using metformin (adjusted HR [aHR] 0.64, 95% CI 0.45–0.89, p = 0.009). In three studies evaluating patients with EC and T2DM (n = 2637), metformin use was associated with a significant reduction in OM (aHR 0.50,
95%CI 0.34–0.74, p = 0.0006). There was low to moderate heterogeneity of adjusted effects across studies.
There was no information about the effect of metformin on cancer-specific mortality,
disease progression, or metastases.
Conclusions
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.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to MaturitasAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Epidemiology of endometrial carcinoma: etiologic importance of hormonal and metabolic influences.Adv. Exp. Med. Biol. 2017; 943: 3-46
- Diabetes mellitus and risk of endometrial cancer: a meta-analysis.Diabetologia. 2007; 50: 1365-1374
- Serum estrogens and estrogen metabolites and endometrial cancer risk among postmenopausal women.Cancer Epidemiol. Biomark. Prev. 2016; 25: 1081-1089
- Insulin resistance and endometrial cancer risk: a systematic review and meta-analysis.Eur. J. Cancer. 2015; 51: 2747-2758
- Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies.Lancet. 2008; 371: 569-578
- Endometrial cancer and obesity: epidemiology, biomarkers, prevention and survivorship.Gynecol. Oncol. 2009; 114: 121-127
- Diabetes and cause-specific mortality in a prospective cohort of one million U.S. adults.Diabetes Care. 2012; 35: 1835-1844
- Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies.Metabolism. 2013; 62: 922-934
- Type 2 diabetes and cancer: umbrella review of metaanalyses of observational studies.BMJ. 2015; 350: g7607
- Duration of adulthood overweight, obesity, and cancer risk in the Women's Health Initiative: a longitudinal study from the United States.PLoS Med. 2016; 13: e1002081
- Childhood body mass index growth trajectories and endometrial cancer risk.Int. J. Cancer. 2017; 140: 310-315
- Metformin therapy and risk of cancer in patients with type 2 diabetes: systematic review.PLoS ONE. 2013; 8: e71583
- Association of metformin use with cancer incidence and mortality: a meta-analysis.Cancer Epidemiol. 2013; 37: 207-218
- Effects of metformin on endometrial cancer cell growth in vivo: a preoperative prospective trial.Cancer. 2014; 120: 2986-2995
- Measuring the biological effect of presurgical metformin treatment in endometrial cancer.Br. J. Cancer. 2016; 114: 281-289
- Metformin treatment and evolution of endometrial cancer.Climacteric. 2014; 17: 207-209
- The prognostic value of metformin for cancer patients with concurrent diabetes: a systematic review and meta-analysis.Diabetes Obes. Metab. 2014; 16: 707-710
- The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses.2016 (http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp (21 December 2016))
- Preferred reporting items for systematic reviews and metaanalyses: the PRISMA statement.J. Clin. Epidemiol. 2009; 62: 1006-1012
- Meta-analysis in clinical trials.Control. Clin. Trials. 1986; 7: 177-188
- Measuring inconsistency in meta-analyses.BMJ. 2003; 327: 557-560
- Commentary: heterogeneity in meta-analysis should be expected and appropriately quantified.Int. J. Epidemiol. 2008; 37: 1158-1160
- Bias in meta-analysis detected by a simple graphical test.BMJ. 1997; 315: 629-634
- Review Manager (RevMan) [Computer program]. Version 5.1.The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen2011
- Metformin is associated with improved survival in endometrial cancer.Gynecol. Oncol. 2014; 132: 438-442
- Metformin use and endometrial cancer survival.Gynecol. Oncol. 2014; 132: 236-240
- Do endometrial cancer patients benefit from metformin intake?.Ginekol. Pol. 2015; 86: 419-423
- The effect of diabetes and metformin on clinical outcomes is negligible in risk-adjusted endometrial cancer cohorts.Gynecol. Oncol. 2016; 140: 270-276
- Association of metformin use with outcomes in advanced endometrial cancer treated with chemotherapy.PLoS ONE. 2016; 11: e0147145
- The prognostic role of metformin in patients with endometrial cancer: a retrospective study.Eur. J. Obstet. Gynecol. Reprod. Biol. 2016; 203: 291-296
- Survival benefits of metformin for colorectal cancer patients with diabetes: a systematic review and meta-analysis.PLoS ONE. 2014; 9: e91818
- Metformin use and its effect on survival in diabetic patients with advanced non-small cell lung cancer.BMC Cancer. 2016; 16: 633
- Lower risk of cancer in patients on metformin in comparison with those on sulfonylurea derivatives: results from a large population-based follow-up study.Diabetes Care. 2012; 35: 119-124
- Cancer risk associated with use of metformin and sulfonylurea in type 2 diabetes: a meta-analysis.Oncologist. 2012; 17: 813-822
- Prospective study of type 2 diabetes mellitus, anti-diabetic drugs and risk of prostate cancer.Int. J. Cancer. 2017; 140: 611-617
- Metformin does not affect cancer risk: a cohort study in the U.K. Clinical Practice Research Datalink analyzed like an intention-to-treat trial.Diabetes Care. 2014; 37: 2522-2532
- No reduced risk of overall, colorectal, lung, breast, and prostate cancer with metformin therapy in diabetic patients: database analyses from Germany and the UK.Pharmacoepidemiol. Drug Saf. 2015; 24: 865-874
- Cancer mortality reduction and metformin: a retrospective cohort study in type 2 diabetic patients.Diabetes Obes. Metab. 2012; 14: 23-29
- Evidence of a causal association between insulinemia and endometrial cancer: a Mendelian randomization analysis.J. Natl. Cancer Inst. 2015; 107 (pii: djv178)
- Proliferation and metastatic potential of endometrial cancer cells in response to metformin treatment in a high versus normal glucose environment.Oncol. Lett. 2016; 12: 3626-3632
- Regulation of insulin-like growth factor signaling by metformin in endometrial cancer cells.Oncol. Lett. 2014; 8: 1993-1999
- Metformin alters DNA methylation genome-wide via the H19/SAHH axis.Oncogene. 2016; https://doi.org/10.1038/onc.2016.391
- Endometrial cancer: a review and current management strategies.Gynecol. Oncol. 2014; 134: 385-392
- ESMO–ESGO–ESTRO consensus conference on endometrial cancer: diagnosis, treatment and follow-up.Radiother. Oncol. 2015; 117: 559-581
- Surgical and systemic management of endometrial cancer: an international survey.Arch. Gynecol. Obstet. 2015; 291: 897-905
Article info
Publication history
Published online: April 08, 2017
Accepted:
April 3,
2017
Received:
March 31,
2017
Identification
Copyright
© 2017 Elsevier B.V. All rights reserved.
