Elsevier

Gynecologic Oncology

Volume 140, Issue 2, February 2016, Pages 270-276
Gynecologic Oncology

The effect of diabetes and metformin on clinical outcomes is negligible in risk-adjusted endometrial cancer cohorts

https://doi.org/10.1016/j.ygyno.2015.11.019Get rights and content

Highlights

  • PS matching can account for confounders of the effect of metformin use on EC

  • PS-matched diabetics and nondiabetics with EC have similar survival

  • PS-matched metformin users have similar survival to other diabetics with EC

Abstract

Objective

To examine the influence of diabetes and metformin therapy on overall survival (OS) and progression-free survival (PFS) in patients with endometrial cancer (EC) by using propensity score (PS) matching to account for confounding factors.

Methods

We retrospectively identified consecutive patients with stage I–IV EC managed surgically from 1999 through 2008 and stratified patients by diabetes status. PS matching was used to adjust for confounding covariates. OS and PFS were compared between diabetic and nondiabetic matched pairs and between matched pairs of diabetic patients with or without metformin therapy. Cox proportional hazards models were fit to estimate the effects on outcomes.

Results

Among 1303 eligible patients (79% stage I, 28% grade 3), 277 (21.3%) had a history of diabetes. Among diabetic patients, treatment consisted of metformin in 116 (41.9%); 57 (20.6%) had other oral agents, 51 (18.4%) insulin with or without other oral agents, and 53 (19.1%) diet modification only. For PS-matched diabetic and nondiabetic patients with EC, OS (hazard ratio [HR], 1.01; 95% CI, 0.72–1.42) and PFS (HR, 1.01; 95% CI, 0.60–1.69) were similar between matched subsets. No differences in OS and PFS were observed when comparing PS-matched metformin users with nondiabetic patients (OS HR, 1.03; 95% CI, 0.57–1.85; PFS HR, 1.14; 95% CI, 0.49–2.62) or with other diabetic patients (OS HR, 0.61; 95% CI, 0.30–1.23; PFS HR, 1.06; 95% CI, 0.34–3.30).

Conclusions

When adjusted for confounding covariates, OS and PFS are similar between diabetic and nondiabetic patients with EC and between metformin users and nonusers or nondiabetic patients.

Introduction

Endometrial cancer (EC) is the third most common gynecologic malignancy worldwide after breast and cervical cancers [1]. The age-adjusted incidence of EC continues to increase in parallel with progression of the epidemic of obesity and physical inactivity [2]. Diabetes mellitus (DM) is a well-known risk factor for EC, with similar prevalence in both type I and II EC [3], [4]. The paradigm of obesity, DM, and insulin resistance may have a critical role in the pathogenesis of EC [5], [6]. Additionally, diabetic women with EC appear to have an increased risk of all-cause mortality compared with nondiabetic women [6]. It has been suggested that whereas insulin resistance and DM may facilitate the initiation and progression of EC, effective DM control may prevent or modulate EC [7].

Metformin is an oral insulin-sensitizing agent used as first-line therapy for type II DM [8]. It inhibits hepatic gluconeogenesis and enhances insulin sensitivity and glucose utilization in peripheral tissues [9]. In vitro data have shown that metformin inhibits growth and decreases invasion and metastasis of EC cell lines [10], [11]. Furthermore, the inhibition of oxidative phosphorylation and modulation of the mTOR pathway by metformin suggests that it has potential therapeutic benefits in EC [12]. A multi-institutional study recently showed that metformin use was associated with improvement in recurrence-free survival and overall survival in patients with EC [13]. The survival benefits of metformin have been particularly highlighted in nonendometrioid EC subtypes, which suggests a role for its use in adjuvant therapy for type II EC [14]. It is unclear whether the benefits of metformin in diabetic patients with EC are attributed to the direct antineoplastic effects of the drug, alteration in the metabolic and hormonal milieu, or modification of underlying patient- and disease-specific factors. The aim of this study was to investigate the effects of metformin on overall survival (OS) and progression-free survival (PFS) in patients with EC after controlling for multiple confounding patient-, disease-, and treatment-specific factors.

Section snippets

Study patients

We retrospectively searched our patient database for the records of all patients who underwent primary surgical intervention for EC at Mayo Clinic, Rochester, Minnesota, from January 1, 1999, through December 31, 2008. Patients who received neoadjuvant chemotherapy, had synchronous invasive cancers, or who denied access to their medical information for research purposes were excluded. The study was approved by the Mayo Clinic Institutional Review Board.

Data collection

As in a prior report addressing the

Results

A total of 1415 patients underwent surgery for EC during the study period. After exclusion of patients with synchronous invasive cancers, receipt of neoadjuvant therapy, or without consent for research, 1303 patients were evaluable. Among the 1303 patients, 277 (21.3%) had a preexisting diagnosis of DM at the time of EC diagnosis, and 1026 (78.7%) were not diabetic. Among patients with DM, 116 (41.9%) were being treated with metformin, 57 (20.6%) with other oral agents, 51 (18.4%) with insulin

Discussion

Worldwide, approximately 400 million people have a diagnosis of DM, with 85% to 95% characterized as type II DM [23]. Multiple studies have suggested an association between type II DM and risk of and mortality from liver, pancreatic, colorectal, breast, and endometrial cancer [24]. However, the evidence to support this conclusion has been criticized for its methodological limitations and lack of robustness [25], [26], [27]. From an epidemiologic perspective, the development of EC has been

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

Funding source: No specific intra- or extramural funding was obtained.

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  • Cited by (0)

    Portions of this manuscript have been published in AlHilli et al. [15]. Used with permission.

    1

    Reprints: Division of Gynecologic Surgery, Mayo Clinic, 200 First St. SW, Rochester, MN 55905, United States.

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