Association of metformin use with cancer incidence and mortality: A meta-analysis
TL;DR: Metformin can reduce the incidence of overall cancer, liver cancer, pancreatic cancer, colorectal cancer and breast cancer as well as the mortality of Overall cancer, Liver cancer and Breast cancer.
About: This article is published in Cancer Epidemiology.The article was published on 2013-06-01. It has received 242 citations till now. The article focuses on the topics: Cancer & Breast cancer.
Citations
More filters
TL;DR: The link between metformin and cancer, the potential for met formin in oncology, and limitations of currently available evidence are outlined.
Abstract: Patients with diabetes mellitus are at increased risk of cancer development Metformin is a well-established, effective agent for the management of type 2 diabetes mellitus Epidemiological studies have identified an association between metformin use and a beneficial effect on cancer prevention and treatment, which has led to increasing interest in the potential use of metformin as an anticancer agent Basic science has provided a better understanding of the mechanism of action of metformin and the potential for metformin to modulate molecular pathways involved in cancer cell signaling and metabolism This article outlines the link between metformin and cancer, the potential for metformin in oncology, and limitations of currently available evidence
368 citations
Cites background from "Association of metformin use with c..."
...In contrast, no strong associations between metformin use and the risk of developing breast, prostate, lung, or ovarian cancer have been found (43, 61)....
[...]
TL;DR: It is suggested that adjuvant metformin could have beneficial effects, particularly on cancer outcomes in colorectal and prostate cancer.
315 citations
TL;DR: The role of metformin as a potential cancer treatment is reviewed to critically review the results of a small number of completed trials.
Abstract: // Young Kwang Chae 1,2,3 , Ayush Arya 3 , Mary-Kate Malecek 3 , Daniel Sanghoon Shin 4 , Benedito Carneiro 1,2,3 , Sunandana Chandra 1,2,3 , Jason Kaplan 1,2,3 , Aparna Kalyan 1,2,3 , Jessica K. Altman 1,2,3 , Leonidas Platanias 1,2,3,5 and Francis Giles 1,2,3 1 Northwestern Medicine Developmental Therapeutics Institute, Chicago, IL, USA 2 Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, USA 3 Northwestern University Feinberg School of Medicine, Chicago, IL, USA 4 David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA 5 Division of Hematology-Oncology, Department of Medicine, Jesse Brown VA Medical Center, Chicago, IL, USA Correspondence to: Young Kwang Chae, email: // Keywords : metformin, clinical trials, cancer Received : September 20, 2015 Accepted : March 06, 2016 Published : March 19, 2016 Abstract In recent years, several studies have presented evidence suggesting a potential role for metformin in anti-cancer therapy. Preclinical studies have demonstrated several anticancer molecular mechanisms of metformin including mTOR inhibition, cytotoxic effects, and immunomodulation. Epidemiologic data have demonstrated decreased cancer incidence and mortality in patients taking metformin. Several clinical trials, focused on evaluation of metformin as an anti-cancer agent are presently underway. Data published from a small number of completed trials has put forth intriguing results. Clinical trials in pre-surgical endometrial cancer patients exhibited a significant decrease in Ki67 with metformin monotherapy. Another interesting observation was made in patients with breast cancer, wherein a trend towards improvement in cancer proliferation markers was noted in patients without insulin resistance. Data on survival outcomes with the use of metformin as an anti-cancer agent is awaited. This manuscript will critically review the role of metformin as a potential cancer treatment.
252 citations
Cites background from "Association of metformin use with c..."
...However, no significant correlation could be derived between the use of metformin and incidence of prostate cancer [29]....
[...]
TL;DR: Examination of metformin’s chemopreventive potential is examined by outlining relevant mechanisms of action, the most recent epidemiologic evidence, and recently completed and ongoing clinical trials.
Abstract: Multiple epidemiological studies have documented an association between metformin, used for treatment of type 2 diabetes, and reduced cancer incidence and mortality. Cell line models may not accurately reflect the effects of metformin in the clinical setting. Moreover, findings from animal model studies have been inconsistent, whilst those from more recent epidemiological studies have tempered the overall effect size. The purpose of this review is to examine metformin's chemopreventive potential by outlining relevant mechanisms of action, the most recent epidemiologic evidence, and recently completed and ongoing clinical trials. Although repurposing drugs with excellent safety profiles is an appealing strategy for cancer prevention and treatment in the adjuvant setting, there is no substitute for well-executed, large randomised clinical trials to define efficacy and determine the populations that are most likely to benefit from an intervention. Thus, enthusiasm remains for understanding the role of metformin in cancer through ongoing clinical research.
221 citations
TL;DR: Evaluated data exists to support a high level of evidence for the benefit of hypoxic modification, but such hypoxia modification still has no impact on general clinical practice.
Abstract: Since the initial observations made at the beginning of the last century, it has been established that solid tumors contain regions of low oxygenation (hypoxia). Tumor cells can survive in these hypoxic conditions and are a major factor in tumor radioresistance. This significance has resulted in hypoxia becoming the most cited biological topic in translational radiation oncology. Identifying hypoxic cells in human tumors has become paramount, and the ability to do this has been improved by the help of new imaging techniques and the use of predictive gene profiles. Substantial data confirm the presence of hypoxia in many types of human tumors, although with considerable heterogeneity among individual tumors. Various approaches have been investigated for eliminating the hypoxic population. These include increasing oxygen availability, directly radiosensitizing or killing the hypoxic cells, indirectly affecting them by targeting the tumor vascular supply, increasing the radiation dose to this resistant population, or by using radiation with a high linear energy transfer, for which hypoxia is believed to be less of an issue. Many of these approaches have undergone controlled clinical trials during the last 50 years, and the results have shown that hypoxic radiation resistance can indeed be overcome. Thus, ample data exists to support a high level of evidence for the benefit of hypoxic modification. However, such hypoxic modification still has no impact on general clinical practice. In this review we summarize the biological rationale, and the current activities and trials, related to identifying and overcoming hypoxia in modern radiotherapy.
219 citations
Cites background from "Association of metformin use with c..."
...this agent is already used clinically in treating diabetes and may be associated with decreased rates of some cancer types [36], it is still too early to say whether this will be effective at decreasing tumor hypoxia in patients....
[...]
References
More filters
TL;DR: A new quantity is developed, I 2, which the authors believe gives a better measure of the consistency between trials in a meta-analysis, which is susceptible to the number of trials included in the meta- analysis.
Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice?
Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.
Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4
Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
45,105 citations
"Association of metformin use with c..." refers methods in this paper
...heterogeneity (I(2) > 50%) [24], the DerSimonian and Laird random effect model (REM) was adopted as the pooling method, otherwise, the fixed effect model (FEM) was used as the pooling method....
[...]
TL;DR: Funnel plots, plots of the trials' effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials.
Abstract: Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure
37,989 citations
"Association of metformin use with c..." refers methods in this paper
...The small-study effect in terms of publication bias was estimated using Egger’s linear regression test [26]....
[...]
TL;DR: Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with met formin abolished most of this excess risk.
Abstract: Aims/hypothesis The risk of developing a range of solid tumours is increased in type 2 diabetes, and may be influenced by glucose-lowering therapies. We examined the risk of development of solid tumours in relation to treatment with oral agents, human insulin and insulin analogues. Methods This was a retrospective cohort study of people treated in UK general practices. Those included in the analysis developed diabetes >40 years of age, and started treatment with oral agents or insulin after 2000. A total of 62,809 patients were divided into four groups according to whether they received monotherapy with metformin or sulfonylurea, combined therapy (metformin plus sulfonylurea), or insulin. Insulin users were grouped according to treatment with insulin glargine, long-acting human insulin, biphasic analogue and human biphasic insulin. The outcome measures were progression to any solid tumour, or cancer of the breast, colon, pancreas or prostate. Confounding factors were accounted for using Cox proportional hazards models. Results Metformin monotherapy carried the lowest risk of cancer. In comparison, the adjusted HR was 1.08 (95% CI 0.96–1.21) for metformin plus sulfonylurea, 1.36 (95% CI 1.19–1.54) for sulfonylurea monotherapy, and 1.42 (95% CI 1.27–1.60) for insulin-based regimens. Adding metformin to insulin reduced progression to cancer (HR 0.54, 95% CI 0.43–0.66). Theriskforthoseonbasalhumaninsulin alone vs insulin glargine alone was 1.24 (95% CI 0.90–1.70). Compared with metformin, insulin therapy increased the risk of colorectal (HR 1.69, 95% CI 1.23–2.33) or pancreatic cancer(HR 4.63,95% CI2.64–8.10),but did not influencethe riskofbreastorprostatecancer.Sulfonylureaswereassociated with a similar pattern of risk as insulin. Conclusions/interpretation Those on insulin or insulin secretagogues were more likely to develop solid cancers than those on metformin, and combination with metformin abolished most of this excess risk. Metformin use was associated with lower risk of cancer of the colon or pancreas, but did not affect the risk of breast or prostate cancer. Use of insulin analogues was not associated with increased cancer risk as compared with human insulin.
1,068 citations
"Association of metformin use with c..." refers background in this paper
...88) Place of residence, and use of other medications (aspirin, cholesterol-lowering or antihypertensive drugs) Currie CJ [21], UK, 2009 Retrospective cohort study of diabetics (diagnosed >40 years of age) Metformin monotherapy vs....
[...]
...Different from these two involving people without diabetes, studies restricted to diabetes patients [21,32,53,55], thus minimizing the potential confounding effect of diabetes found a neutral role for metformin....
[...]
TL;DR: Results suggest that metformin use may be associated with a reduced risk of cancer in people with type 2 diabetes, and a randomized trial is needed to assess whether met formin is protective in a population at high risk for cancer.
Abstract: OBJECTIVE The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels. We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes. RESEARCH DESIGN AND METHODS In an observational cohort study using record-linkage databases and based in Tayside, Scotland, U.K., we identified people with type 2 diabetes who were new users of metformin in 1994–2003. We also identified a set of diabetic comparators, individually matched to the metformin users by year of diabetes diagnosis, who had never used metformin. In a survival analysis we calculated hazard ratios for diagnosis of cancer, adjusted for baseline characteristics of the two groups using Cox regression. RESULTS Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively ( P CONCLUSIONS These results suggest that metformin use may be associated with a reduced risk of cancer. A randomized trial is needed to assess whether metformin is protective in a population at high risk for cancer.
1,001 citations
TL;DR: A comprehensive literature search and meta-analysis of epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients found that the inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer.
Abstract: Metformin, an insulin-lowering agent, has been associated with decreased cancer risk in epidemiologic studies in diabetic patients. We performed a comprehensive literature search and meta-analysis of epidemiologic studies to assess the effect of metformin on cancer incidence and mortality in diabetic patients, using Pubmed, ISI Web of Science, Embase, and the Cochrane library until May 2009, with no language or time restrictions. Independent reports with sufficient information to allow risk estimation of cancer risk/mortality and a measure of uncertainty were reviewed and cross-checked independently by three investigators. Eleven studies were selected for relevance in terms of intervention, population studied, independence, and reporting of cancer incidence or mortality data, reporting 4,042 cancer events and 529 cancer deaths. A 31% reduction in overall summary relative risk (0.69; 95% confidence interval, 0.61-0.79) was found in subjects taking metformin compared with other antidiabetic drugs. The inverse association was significant for pancreatic and hepatocellular cancer, and nonsignificant for colon, breast, and prostate cancer. A trend to a dose-response relationship was noted. Metformin is associated with a decreased risk of cancer incidence compared with other treatments among diabetic patients. Given the retrospective nature of most studies and the possibility that the control treatments increase risk, phase II trials are needed before large cancer prevention trials are launched.
831 citations