Contributed equally
The association between metformin and the lung cancer risk of patients with type 2 diabetes mellitus (T2DM) remains controversial. Therefore, the present meta-analysis on epidemiological studies was performed to explore this issue. A comprehensive literature search was conducted for all the potential studies addressing metformin use and lung cancer risk by utilizing Pubmed, CBM and ISI Web of Science using the Mesh terms: ‘Metformin,’ or ‘biguanides’ and ‘lung cancer,’ or ‘neoplasms’. The reference lists were also inspected. Eight observational studies, including 17,997 lung cancer patients, were eventually selected, which contained seven case-control and one cohort study. Compared to other antidiabetic agents, metformin was significantly associated with the 16% reduction of lung cancer risk in type 2 diabetic patients [relative risk (RR)=0.84; 95% confidence interval (95% CI), 0.73-0.97]. In the sensitivity analysis by separately excluding the study with a high weight or lower quality, the results did not materially change. Subsequently, subgroup analysis was performed on the type of study design, unadjusted or adjusted hazard ratio, quality of enrolled studies, duration of treatment, country and control drugs. The magnitude of lung cancer risk reduction was strengthened when compared to sulfonylureas (RR=0.79; 95% CI, 0.83-0.9), without significant heterogeneity (Q-value=2.98, P=0.085). In conclusion, the present analysis supported that the use of metformin significantly decreased the risk of lung cancer among patients with T2DM. However, further studies are required to confirm these findings.
Diabetic mellitus is a worldwide common metabolic disease. Abundant evidence indicated that diabetic mellitus was associated not only with cardiovascular diseases, nephropathy and retinopathy, but also with the development of numerous types of cancer, including lung, liver, colorectal, kidney and breast (
Glucose lowering drugs are possibly associated with either an increased or reduced risk of cancer (
Previous studies have confirmed that metformin inhibits tumor cell proliferation and improves the survival of cancer patients (
Lung cancer has become one of the leading causes of cancer-related mortality in numerous countries. Recent data have suggested an association of metformin use with decreased lung cancer risk of type 2 diabetic patients (
A comprehensive literature search was performed for all the studies addressing the association between metformin use and lung cancer risk. Electronic databases searched included Pubmed, CBM and ISI Web of Science until October 2013, without language restrictions. The Mesh terms and/or the text words used included ‘metformin’ or ‘biguanides’ and lung ‘cancer’ or ‘neoplasms’. In addition, the reference lists were also inspected.
The inclusion criteria of a study in the meta-analysis included the following: i) Epidemiological studies, which included case-control or cohort studies; ii) designed to evaluate the association between metformin and risk of lung cancer in diabetic patients; and iii) contained sufficient information to allow adequate estimation of hazard ratio (HR), odds ratio (OR), or relative risk (RR) and 95% confidence interval (95% CI) to estimate the lung cancer risk with diabetes using metformin compared to other antidiabetic treatments or no treatment. When two independent control groups were set in the same case-control study, the study was treated as two separate studies, only considering the limited relevant studies enrolled.
The enrolled studies were evaluated by two independent authors (Ning Zhu and Yuanyuan Zhang). For the included studies, these data were extracted: First author, year of publication, country or area, study design, source of cases, number of total participants or lung cancer cases, study time or follow-up time, unadjusted and adjusted RR with their 95% CIs and the confounding factors, which had been adjusted. To ascertain the validity of the eligible studies, the quality of each study was appraised in reference to the Newcastle-Ottawa statement (
The value of RR was adopted for the cohort studies or OR for the case-control studies to evaluate the risk estimate in the meta-analysis. When the adjusted RRs were available, they were used to estimate the association. Otherwise, the unadjusted RRs were adopted. The adjusted HR was pooled using the DerSimonian and Laird statistic. Stratified analyses were conducted according to type of study design, type of HRs, study quality, country, duration of treatment or control drugs. Studies were pooled and weighted according to inverse variance using the random-effects model of DerSimonian and Laird. P<0.05 was considered to indicate a statistically significant difference for all the tests. Sensitivity analysis was conducted by sequentially excluding one study with a high weight or low quality. Finally, the publication bias was detected using the Begg's funnel plot and Egger's regression asymmetry test. All analyses were performed using Stata version 11.0 (StataCorp, College Station, TX, USA).
The participant flow diagram for the study inclusion in the meta-analysis is shown in
These studies were conducted in six countries, which were Canada (
The baseline characteristics of these enrolled studies are demonstrated in
In order to validate the results of the overall analysis and find the possible source of statistical heterogeneity among studies, the subgroup analysis was performed. As mentioned above, subgroup analysis was conducted according to several different variables, which are shown in
A statistically significant reduction of the lung cancer risk in type 2 diabetic patients using metformin was obtained when the studies were restricted to case-control studies or studies with high quality (RR=0.85; 95% CI, 0.73-0.99; and RR=0.74; 95% CI, 0.62-0.89), which were consistent with the result of the overall analysis. In the subgroup analysis regarding the unadjusted HR (
As shown in
Increasing evidence has strengthened that hyperglycemia, obesity-related insulin resistance and secondary hyperinsulinemia are important regulators of the development of cancer (
In the present meta-analysis, metformin therapy for type 2 diabetes patients was demonstrated to decrease the lung cancer incidence, compared to other antidiabetic agents. This result was comparable to that of a previously published meta-analysis by Noto
Furthermore, in order to further inspect the stability of the results and find the possible source of statistical heterogeneity, subgroup analysis was performed according to several variables. Each study provided the adjusted HR. All the studies were adjusted for age and gender, but other potential confounders, such as smoking status, body mass index (BMI), dosage of metformin and comorbidity, were not matched in certain enrolled studies, which may cause the material change of the final results. Unadjusted HR was retrieved from three studies (
Several limitations of the present meta-analysis should be addressed. First, the reliance of the results was weakened by the drawbacks that are inherent to retrospective observational studies, such as possible investigator and recall biases. All the eight studies enrolled were retrospective. Details of metformin dose, duration and other information on potential confounders and risk factors were incomplete, some of which were not fully adjusted in several studies. For example, tobacco use is a well-known risk factor, but only one study evaluated the effect of tobacco use on the lung cancer risk of diabetes patients with metformin therapy (
In conclusion, the present meta-analysis has indicated that the use of metformin significantly decreased the lung cancer risk of patients with T2DM. However, further investigations, particularly randomized controlled trials, are required to confirm the association.
Flow diagram of the study selection. NSCLC, non-small cell lung cancer.
Forest funnel of the pooled relative risks for metformin treatment and lung cancer risk in diabetic patients. (A) Overall analysis. (B and C) Sensitivity analysis excluding one study with a high weight or lower quality, respectively.
Publications bias detected by (A) Begg's funnel plot and (B) Egger's funnel plot. s.e., standard error; RR, relative risk.
Baseline characteristics of the included studies.
Unadjusted | Adjusted | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|
First author (year) | Country | Study design | Duration of observation, years | No. of metformin users (lung cancer Source patients) | Source of case | Matched factor | HR | 95% CI | HR | 95% CI | Study | quality |
Wang (2013) | Taiwan | Cohort | 1998-2009 | 37,055 (162) | National Health Insurance datasets | Age, gender and occupation | NA | NA | 1.11 | 0.94-1.47 | 4 | ( |
Smiechowski (2013) | Canada | Nested case-control | Mean follow-up, 5.6 | 115,923 (1,061) | UK General Practice Research Database | Age, gender, calender time of cohort entry, duration of follow up | 0.97 | NA | 0.94 | 0.76-1.17 | 7 | ( |
Lai (2012) | Taiwan | Retro-spective case-control | 2000-2008 | 19,624 (96) | National Health Research Institutes in Taiwan | Age, gender | 0.43 | 0.29-0.63 | 0.55 | 0.37-0.82 | 7 | ( |
Hsieh |
Taiwan | Case-control | 2000-2008 | 3,963 (1,226) | Taiwan's National Health Insurance Medical Claims Database | Age, gender | NA | NA | 0.95 | 0.46-1.95 | 6 | ( |
Hsieh |
Taiwan | Case-control | 2000-2008 | 3,963 (1,226) | Taiwan's National Health Insurance Medical Claims Database | Age, gender | NA | NA | 0.64 | 0.45-0.9 | 6 | ( |
(2012) control (1,226) National Health | ||||||||||||
Mazzone (2012) | USA | Retro-spective case-control | 2001-2011 | 93,939 (522) | Cleveland Clinic Health System | Age, gender smoking history | NA | NA | 0.48 | 0.28-0.81 | 6 | ( |
Ruiter (2012) | The Netherlands | Case-control | 1998-2008 | 85,289 (1,590) | PHARMO Record Linkage System | Age, gender, calendar time, no. of unique drugs used and no. of hospitalizations | NA | NA | 0.87 | 0.84-0.91 | 6 | ( |
Bodmer (2012) | Switzerland | Case-control | 1995-2009 | NA (13,043) | UK-based General Practice Research Database | Age, gender, general practice, same index date and no. of years of active history | 1.07 | 0.87-1.31 | 1.09 | 0.85-1.38 | 6 | ( |
Libby (2009) | Scotland | Cohort | 1993-2003 | 4,085 (297) | Resident Population of Tayside Health Board (Scotland, UK) | Age, gender, BMI, HbA1c, smoking, deprivation, other drug use | 0.49 | 0.32-0.74 | 0.7 | 0.43-1.15 | 6 | ( |
Newcastle-Ottawa star.
The study has separately compared (a) insulin or (b) sulfonylureas with metformin for the effect on lung cancer risk of type 2 diabetic patients. Considering these two independent antidiabetic agents and the limited enrolled studies, this study was treated as two independent case-control studies in the meta-analysis. HR, hazard ratio; 95% CI, 95% confidence interval; NA, not available; BMI, body mass index; HbA1c, hemoglobin A1c.
Results of the subgroup analysis according to different variables.
Pooled RR | Heterogeneity | |||||
---|---|---|---|---|---|---|
Subgroup | No. of studies | Model | RR (95% CI) | P-value | Q-value | P-value |
Type of design of studies | ||||||
Case-control | 8 | Random | 0.85 (0.73–0.99) | 0.04 | 21.32 | 0.003 |
Quality of enrolled study | ||||||
High | 8 | Random | 0.74 (0.62–0.89) | 0.001 | 29.91 | <0.001 |
Unadjusted or adjusted HR | ||||||
Adjusted | 9 | Random | 0.84 (0.73–0.97) | 0.02 | 22.10 | 0.005 |
Unadjusted | 3 | Random | 0.62 (0.33–1.18) | 0.15 | 22.85 | <0.001 |
Country | ||||||
Western | 5 | Random | 0.87 (0.75–1.02) | 0.09 | 9.35 | 0.053 |
Asian | 4 | Random | 0.78 (0.53–1.15) | 0.21 | 12.72 | 0.005 |
Duration of treatment | ||||||
Long-term use |
4 | Random | 0.89 (0.79–1.01) | 0.36 | 11.77 | 0.008 |
Control drugs | ||||||
Control groups use sulfonylureas | 2 | Fixed | 0.79 (0.83–0.9) | 0.000 | 2.98 | 0.085 |
Lai