The effect of metformin and thiazolidindione use on lung cancer in diabetics

BMC Cancer (Impact Factor: 3.36). 09/2012; 12(1):410. DOI: 10.1186/1471-2407-12-410
Source: PubMed


Metformin and the thiazolidinediones (TZDs) may have a protective effect against the development of lung cancer.

Patients with diabetes mellitus (DM) were identified from the electronic medical records of the Cleveland Clinic. Diabetics with lung cancer were identified then verified by direct review of their records. Control subjects were matched with cancer subjects 1:1 by date of birth, sex, and smoking history. The frequency and duration of diabetic medication use was compared between the groups. The cancer characteristics were compared between those with lung cancer who had and had not been using metformin and/or a TZD.

93,939 patients were identified as having DM. 522 lung cancers in 507 patients were confirmed. The matched control group was more likely to have used metformin and/or a TZD (61.0% vs. 41.2%, p < 0.001 for any use; 55.5% vs. 24.6%, p < 0.001 for >24 months vs. 0–12 months). In the group with lung cancer, those who had used metformin alone had a different histology distribution than those who received neither metformin nor a TZD, were more likely to present with metastatic disease (40.8% vs. 28.2%, p = 0.013), and had a shorter survival from the time of diagnosis (HR 1.47, p < 0.005).

The use of metformin and/or the TZDs is associated with a lower likelihood of developing lung cancer in diabetic patients. Diabetics who develop lung cancer while receiving metformin may have a more aggressive cancer phenotype.

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Available from: Anil K Jain, Jan 28, 2014
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    • "Meta-analysis of all 8 observational studies reported that the metformin use was associated with a statistically significant 15% reduction in lung cancer incidence (OR 0.85, 95% CI 0.77 to 0.92 P = 0.003 for heterogeneity) (Figure 2a) [9], [10], [12], [13], [15], [17], [33], [35]. The summary OR of 7 cohort studies was 0.87 (95% CI 0.81 to 0.93). "
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    ABSTRACT: Background Accumulating evidence suggests that hypoglycaemic agents influence lung cancer risk in patients with diabetes. It remains to be fully elucidated whether conventional hypoglycaemic agents (metformin, sulfonylureas, thiazolidinediones [TZDs] or insulin) affect lung cancer incidence in patients with diabetes. Methods We performed a meta-analysis using EMBASE, MEDLINE and Web of Science to search randomised controlled trials (RCTs), cohort studies, and case-control studies published up to October 2013 that assessed the effects of metformin, sulfonylurea, TZDs or insulin on lung cancer risk in subjects with diabetes. Fixed and random effects meta-analysis models were used, and the effect size was expressed as a summary odds ratio (OR) with 95% confidence intervals (CI). The Grades of Research, Assessment, Development and Evaluation (GRADE) approach was applied to define the quality of the evidence. Results Analysis of 15 studies (11 cohort studies, 2 case-control studies, and 2 RCTs) showed that metformin use was associated with a 15% reduction in risk of lung cancer (OR 0.85, 95% CI 0.77 to 0.92), but this finding was not supported by sub-analysis of smoking-adjusted studies (OR 0.84, 95% CI 0.61 to 1.06). Moreover, sulfonylurea or TZDs use was not associated with increased or decreased lung cancer risk, respectively (OR 1.10, 95% CI 0.93 to 1.26), (OR 0.86, 95% CI 0.70 to 1.02). Higher lung cancer risk was related to insulin (OR 1.23, 95% CI 1.10 to 1.35). However, all data from RCTs failed to demonstrate a statistically significant effect. Conclusions This analysis demonstrated that metformin use may reduce lung cancer risk in patients with diabetes but not in a smoking-adjusted subgroup and that insulin use may be associated with an increased lung cancer risk in subjects with diabetes.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "Epidemiological studies (8–10) first suggested a link between metformin and cancer prevention by demonstrating a lower incidence of death from cancer in patients with diabetes mellitus treated with metformin than those treated with other antidiabetic agents. These studies were followed by clinical observations, suggesting a link between metformin and increased pathologically complete response rate by induction chemotherapy in patients with breast cancer (10) as well as lower incidence rate of metastasis and a reduced risk of death in patients with lung cancer (11). These findings triggered a number of in vitro and in vivo experiments, revealing its antiproliferative properties in a variety of cancers (12–20). "
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    ABSTRACT: Cancer chemotherapy, including molecular targeted therapy, has major limitations because it does not kill all the cancer cells; the residual cells survive until they acquire chemoresistance. In the present study, the combined effects of metformin and gefitinib were examined in vivo in a mouse xenograft model, inoculated with a human lung adenocarcinoma cell line that possesses an activating epidermal growth factor receptor mutation. The mechanism of the interaction was further elucidated in vitro. Metformin did not suppress the growth of already established tumors, nor did metformin augment tumor shrinkage by gefitinib. However, metformin significantly suppressed the regrowth of the tumor after effective treatment with gefitinib, suggesting the specific effect of metformin on the residual cells. Cytotoxicity of metformin was characterized by the absence of apoptosis induction and unremarkable cell cycle shift in vitro. The residual cell population after treatment with gefitinib was characterized by enriched cells with high expression of CD133 and CD24. Metformin was still effective on this specific cell population. Targeting residual cells after chemotherapy may represent an effective novel strategy for the treatment of cancer. Elucidating the mechanism of metformin cytotoxicity provides insights into future development of anticancer therapeutics.
    Full-text · Article · Oct 2013 · International Journal of Oncology
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    • "A meta-analysis completed this past year confirms a small, but significant decreased risk of lung (and other) cancers in diabetics treated with thiazolidinediones [93]. A review of patients with diabetes at the Cleveland Clinic found that those who had not been treated with metformin (see mTOR inhibitors section below) and/or thiazolidinediones were more likely to develop lung cancer [94]. An ongoing trial at the Denver VA is evaluating the effect of pioglitazone on lung cancer incidence in smokers [95]. "
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    ABSTRACT: Decreasing the risk of lung cancer, or preventing its development in high-risk individuals, would have a huge impact on public health. The most effective means to decrease lung cancer incidence is to eliminate exposure to carcinogens. However, with recent advances in the understanding of pulmonary carcinogenesis and the identification of intermediate biomarkers, the prospects for the field of chemoprevention research have improved dramatically. Here we review the most recent research in lung cancer chemoprevention-focusing on those agents that have been investigated in human clinical trials. These agents fall into three major categories. First, oxidative stress plays an important role in pulmonary carcinogenesis; and therefore, antioxidants (including vitamins, selenium, green tea extracts, and isothiocyanates) may be particularly effective in preventing the development of lung cancer. Second, inflammation is increasingly accepted as a crucial factor in carcinogenesis, and many investigators have focused on anti-inflammatory agents, such as glucocorticoids, NSAIDs, statins, and PPARγ agonists. Finally, the PI3K/AKT/mTOR pathway is recognized to play a central role in tobacco-induced carcinogenesis, and inhibitors of this pathway, including myoinositol and metformin, are promising agents for lung cancer prevention. Successful chemoprevention will likely require targeting of multiple pathways to carcinogenesis-both to minimize toxicity and maximize efficacy.
    Full-text · Article · Mar 2013 · Cancers
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