Elsevier

Lung Cancer

Volume 78, Issue 2, November 2012, Pages 133-137
Lung Cancer

Metformin does not alter the risk of lung cancer: A case–control analysis

https://doi.org/10.1016/j.lungcan.2012.08.010Get rights and content

Abstract

Background

Metformin use has been linked to a decreased cancer risk. We explored the association between use of metformin or other antidiabetic drugs and the risk of lung cancer.

Methods

We assessed the association between metformin, and other antidiabetic drugs and lung cancer using a case–control analysis in the UK-based General Practice Research Database (GPRD). Cases were people with an incident diagnosis of lung cancer. Up to 6 controls per case were matched on age, sex, calendar time, general practice, and number of years of active history in the GPRD. The contribution of potential confounders including tuberculosis, chronic obstructive pulmonary disease (COPD), diabetes mellitus, and co-morbid conditions to diabetes was evaluated in univariate models, and final results were adjusted for BMI and smoking.

Results

Long-term use (≥40 prescriptions) of metformin was not associated with an altered risk of lung cancer (adj. OR 1.21, 95% CI 0.97–1.50. Long-term use of sulfonylureas was linked to a marginally decreased risk of lung cancer (adj. OR 0.74, 95% CI 0.60–0.90. This risk decrease was observed in men (adj. OR 0.64, 95% CI 0.50–0.83) but not in women (adj. OR 0.97, 95% CI 0.69–1.37) and this risk decrease was not statistically significant in an analysis restricted to diabetic patients only (adj. OR. 0.82, 95% CI 0.65–1.02). Long-term use of insulin was associated with a slightly increased risk of lung cancer (adj. OR 1.33, 95% CI 1.04–1.71); however, no consistent trend across duration strata was observed.

Conclusion

Metformin did not decrease the risk of lung cancer.

Introduction

Lung cancer is one of the leading causes of cancer-related mortality worldwide and accounts for approximately 30% of cancer deaths in the US [1]. Despite advances in early diagnosis and treatment modalities, prognosis remains poor; the five-year survival is only about 15% [2]. Therefore, prevention of lung cancer is of utmost importance and urgent efforts are needed to identify measures, including drug treatment that may be effective in reducing the lung cancer risk.

Diabetes mellitus has been associated with a decreased risk of lung cancer in some [3], [4], [5] but not all studies [6], [7], [8], a finding which may be explained by different smoking habits. Alternatively, since higher body weight has been reported to be related to a decreased risk of lung cancer [3], [9], and since people with diabetes are more often obese, this could explain the lower risk of lung cancer in patients with type 2 diabetes.

Metformin, a widely used oral antidiabetic agent, has been demonstrated to exert anticancer effects [10]. Available evidence from observational and clinical studies has recently been published in a meta-analysis [11]. The antitumor activity of metformin may be explained by two different mechanisms. Firstly, metformin decreases insulin resistance and lowers circulating insulin levels by activating AMP-activated protein kinase (AMPK), leading to decreased hepatic gluconeogenesis [12] and increased uptake of glucose in muscle. Secondly, metformin has been shown to act as a tumor growth inhibitor, at least in part by up-regulation of AMPK activity and by downstream suppression of signaling through the mammalian target of rapamycin (mTOR) [10].

Data from recent basic science studies suggest that metformin inhibits lung cancer cell growth in vitro [13] and in a mouse model [14]. In another investigation, metformin reduced tumor cell burden in a mouse model of tobacco carcinogen-induced carcinogenesis [15]. Additionally, there is some epidemiological evidence available linking use of metformin to a decreased risk of lung cancer [8], and in one retrospective clinical study, use of metformin was associated with a tendency toward better disease control in lung cancer patients [16].

To explore whether use of metformin or other antidiabetic drugs are associated with an altered risk of developing lung cancer in diabetic patients, we conducted a large case–control analysis using the UK-based General Practice Research Database (GPRD). In addition, we assessed the role of diabetes mellitus in lung cancer development.

Section snippets

Data source

Data were derived from the UK-based General Practice Research Database (GPRD) which was established around 1987 and encompasses data on over 7 million individuals [17]. Patients enrolled in participating practices are representative of the UK with regard to age, sex, geographic distribution, and annual turnover rate. General practitioners (GPs) have been trained to record medical information including demographic data, medical diagnoses, hospitalizations, deaths, and drug prescriptions using

Results

We identified a total of 13,043 cases with incident lung cancer and 78,258 matched controls. The mean (±SD) age of cases and controls was 69.0 ± 10.3 years at the index date. Characteristics of patients and controls are displayed in Table 1. Mean (±SD) time of history in the GPRD was 3709 ± 1556 days (10.1 ± 4.3 years). Minimal time of database history was 3.0 years regardless of using the original or shifted index date.

Use of metformin was neither consistently associated with an altered risk of lung

Discussion

The results from our large observational study suggest that metformin use is not linked to a decreased risk of lung cancer, in either men or women. Our findings remained closely similar in various predefined sensitivity analyzes, a finding which further strengthens the conclusion that there is no association between use of metformin and lung cancer. Short-term antidiabetic drug use did not materially differ across the analyzes with shifted and original index dates indicating that preclinical

Funding

This work was partially funded by the Swiss Cancer League (Krebsliga Schweiz) and the University of Basel (MB, CRM).

Conflict of interest

None.

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