Metformin therapy and the risk of colorectal adenoma in patients with type 2 diabetes: A meta-analysis

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diabetes mellitus 1 endocrinologydiseases
hyperglycemia 1 endocrinologydiseases
hyperinsulinemia 2 endocrinologydiseases
metformin 76 endocrinologydiseasesdrugs
obesity 3 endocrinologydiseases

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metformin 596 (collection): 1/2017Publication date (epub): 11/2016AbstractBackgroundExisting data evaluating the impact of metformin on the colorectal adenoma (CRA) risk in patients suffering from type 2 diabetes (T2D) are limited and
metformin 817 controversial. We therefore summarized the studies currently available and assessed the relationship between metformin treatment and risk of CRA in T2D patients.MethodsWe systematically searched databases for eligible studies
metformin 962 patients.MethodsWe systematically searched databases for eligible studies that explored the impact of metformin treatment on the occurrence of CRA in T2D patients from inception to June 2016. The summary odds ratio
metformin 1357 performed.ResultsSeven studies involving 7178 participants met the inclusion criteria. The pooling showed that metformin therapy has a 27% decrease in the CRA risk (OR, 0.73; 95% CI, 0.58 - 0.90). In subgroup analysis, we
metformin 1482 27% decrease in the CRA risk (OR, 0.73; 95% CI, 0.58 - 0.90). In subgroup analysis, we detected that metformin exhibits significant chemoprevention effects in Asia region (OR, 0.68; 95% CI, 0.48 - 0.96). Similar
metformin 1805 0.86 and OR, 0.70; 95% CI, 0.58 - 0.84, respectively). Of note, an inverse relationship was noted that metformin therapy may result in a significant decrease in the advanced adenoma risk (OR, 0.52; 95% CI, 0.38 -
metformin 2068 results remained robust in multiplesensitivity analyses.ConclusionsThis meta-analysis indicates that metformin therapy is correlated with a significant decrease in the risk of CRA and advanced adenoma in T2D patients.
metformin 2267 in T2D patients. Further confirmatory studies are warranted.Existing data evaluating the impact of metformin on the colorectal adenoma (CRA) risk in patients suffering from type 2 diabetes (T2D) are limited and
metformin 2488 controversial. We therefore summarized the studies currently available and assessed the relationship between metformin treatment and risk of CRA in T2D patients.We systematically searched databases for eligible studies
metformin 2626 T2D patients.We systematically searched databases for eligible studies that explored the impact of metformin treatment on the occurrence of CRA in T2D patients from inception to June 2016. The summary odds ratio
metformin 3014 performed.Seven studies involving 7178 participants met the inclusion criteria. The pooling showed that metformin therapy has a 27% decrease in the CRA risk (OR, 0.73; 95% CI, 0.58 – 0.90). In subgroup analysis,
metformin 3141 decrease in the CRA risk (OR, 0.73; 95% CI, 0.58 – 0.90). In subgroup analysis, we detected that metformin exhibits significant chemoprevention effects in Asia region (OR, 0.68; 95% CI, 0.48 – 0.96). Similar
metformin 3470 and OR, 0.70; 95% CI, 0.58 – 0.84, respectively). Of note, an inverse relationship was noted that metformin therapy may result in a significant decrease in the advanced adenoma risk (OR, 0.52; 95% CI, 0.38 –
metformin 3725 however, the results remained robust in multiple sensitivity analyses.This meta-analysis indicates that metformin therapy is correlated with a significant decrease in the risk of CRA and advanced adenoma in T2D patients.
metformin 5985 Encouragingly, several preclinical studies have shown that conventional antidiabetic medication, especially metformin , may modify the risk of CRC. Metformin is a biguanide derivative that is frequently used as the first-line
metformin 6383 increasing glucose absorption by muscle tissues [[20], [21]]. Unlike other oral antidiabetic drugs, metformin does not stimulate insulin secretion directly and has been recommended as the initial treatment of diabetes
metformin 6522 secretion directly and has been recommended as the initial treatment of diabetes [[22]]. Importantly, metformin is well tolerated in most subjects with a good safety profile and low cost, thereby being easily accessible
metformin 6760 for large populations. Experimental data obtained from in vitro and animal studies identified that metformin can suppress proliferation of cultured cancer cells and lower cancer risk [[23]]. In addition, previous
metformin 6902 cultured cancer cells and lower cancer risk [[23]]. In addition, previous studies have indicated that metformin is involved in the tumor-suppressor pathway by inhibiting lipogenic pathways and stimulating liver kinase
metformin 7241 mammalian target of rapamycin (mTOR) pathway [[24], [25]]. Similarly, in vitro experiments have shown that metformin triggers cell growth arrest [[26]], induces cell apoptosis [[27]], and inhibits invasive properties
metformin 7462 cells [[28]]. Animal experiments concur with these findings. Non-diabetic mouse model has shown that metformin suppresses the polyp growth [[29]] and colonic epithelial proliferation [[30]], suggesting a promising
metformin 7697 chemoprevention against CRC. In addition, a clinical trial in humans showed that oral administration of metformin at a low-dose of 250 mg/day is safe and able to inhibit the colorectal aberrant crypt foci (ACF) formation
metformin 7940 regarded as a very useful CRC biomarker [[32]].However, existing data evaluating the association between metformin and CRA are limited and controversial. Thus, a meta-analysis was performed in this paper to summarize
metformin 8105 meta-analysis was performed in this paper to summarize literature available to date to assess the impact of metformin treatment on the CRA risk in patients suffering from T2D.RESULTSSearch resultsA flowchart describing
metformin 8698 evaluation. After reviewing the full text, 7 observational studies assessing the relationship between metformin therapy and CRA risk in T2D patients were selected for eligibility [[33]–[39]]. One meeting abstract
metformin 9693 selected studies were published between 2008 and 2015. Seven studies investigated the relationship between metformin treatment and the risk of CRA in T2D patients, of which five studies performed adjusted odds ratio (OR)
metformin 10062 (3/5), insulin use (2/5), alcohol use (2/5). In addition, four studies reported the relationship between metformin treatment and the advanced adenoma risk [[37], [38], [40], [41]]. Of these four studies, only two studies
metformin 10660 Table S1.Table 1Main characteristics of studies included in the meta-analysis of association between metformin therapy and risk of CRA in T2D patientsSourceaRecruitment periodStudy typeGender (% male)Age (mean ±
metformin 12699 significant relationship. In a pooled analysis of all seven studies, compared with treatment without metformin , treatment with metformin was correlated significantly with the reduction in CRA incidence by 27% (OR,
metformin 12725 In a pooled analysis of all seven studies, compared with treatment without metformin, treatment with metformin was correlated significantly with the reduction in CRA incidence by 27% (OR, 0.73; 95% CI, 0.58 –
metformin 13006 0.06) (Figure 2).Figure 2Forest plot for the meta-analysis of studies examining the association between metformin treatment and risk of CRA in T2D patientsCI, confidence interval; IV, inverse variance; SE, standard
metformin 13290 adenomaOnly four studies reported the incidence of colorectal advanced adenoma in T2D patients with metformin therapy [[36]–[38], [40]]. Of these four studies, two studies showed an apparent chemoprotective association.
metformin 13492 chemoprotective association. In contract, the other two studies did not show statistical differences between metformin therapy group and non-metformin therapy group. Pooling showed that there was statistically significant
metformin 13524 the other two studies did not show statistical differences between metformin therapy group and non- metformin therapy group. Pooling showed that there was statistically significant association between metformin
metformin 13625 non-metformin therapy group. Pooling showed that there was statistically significant association between metformin therapy and colorectal advanced adenoma (OR, 0.52; 95% CI, 0.38 – 0.72; P <0.01), with insignificant
metformin 13881 0.23) (Figure 3).Figure 3Forest plot for the meta-analysis of studies examining the association between metformin treatment and risk of advanced adenoma in T2D patientsCI, confidence interval; IV, inverse variance;
metformin 14268 studies (Table 2). A reduction with statistical significance in CRA risk in T2D patients treated with metformin was obtained in studies conducted in Korea region or studies with adjusted ORs (OR, 0.68; 95% CI, 0.48-0.96;
metformin 14872 subgroup analyses regarding study quality, high-quality studies revealed an inverse relationship between metformin therapy and CRA risk in T2D patients (OR, 0.70; 95% CI, 0.58 – 0.84; P <0.01), with null heterogeneity
metformin 15192 group (OR, 0.56; 95% CI, 0.17 – 1.86; P = 0.34).Table 2Subgroup analyses of relationship between metformin therapy and risk of CRA in T2D patientsTest of RelationshipTest of HeterogeneitySubgroupNo. of studiesNo.
metformin 16138 specific study would change the magnitude or direction of the summary effect for the correlation between metformin therapy and CRA risk in T2D patients (OR, 0.67 – 0.78, P <0.05). Additionally, the significant association
metformin 17054 most contemporary meta-analysis, to the best of our knowledge, demonstrating an association between metformin therapy and CRA risk in T2D patients. The findings of the current study demonstrated that metformin
metformin 17154 metformin therapy and CRA risk in T2D patients. The findings of the current study demonstrated that metformin therapy was reversely correlated with the decrease in the risk of CRA in T2D patients, with an about
metformin 17301 the decrease in the risk of CRA in T2D patients, with an about 27% reduction compared with the non- metformin therapy. Moreover, we identified for the first time that there was a statistical significant inverse
metformin 17433 identified for the first time that there was a statistical significant inverse relationship between metformin therapy and the colorectal advanced adenoma risk in T2D patients. No substantial difference in pooled
metformin 17959 criteria. It should be noted that this meta-analysis included only three studies exploring the effect of metformin on the risk of CRA, comprising 3745 subjects. Our meta-analysis had a markedly larger sample size than
metformin 18133 had a markedly larger sample size than this study; we also evaluated the advanced adenoma risk with metformin therapy, and our study was up to date.In the subgroup analyses, the results were significantly affected
metformin 18390 adjusted confounders, and study quality. When stratifying studies by location, it was demonstrated that metformin therapy was associated with a significant decrease in CRA risk in Asia, while no significant association
metformin 18586 significant association was found in North America. Of interest, the antineoplastic relationship between metformin therapy and CRA risk was more evident in Asian people. Differences observed in the Asian and Western
metformin 20513 receptor, or IGF-1 receptor, thereby activating multiple signaling pathways [[50], [51]]. However, metformin therapy decreases levels of IGF-1, improves insulin resistance in peripheral tissues, and alleviates
metformin 20838 the improvement of insulin sensitivity, the promotion of weight loss, and other systematic effects, metformin has tumor-cell specific effects [[54]]. It has been well established in experimental studies that metformin
metformin 20946 metformin has tumor-cell specific effects [[54]]. It has been well established in experimental studies that metformin exerts the anti-cancer activity through activation of AMPK and subsequent inhibition of the mTOR pathway,
metformin 21218 signaling and is frequently activated in cancer cells [[55]]. Furthermore, in vitro studies have shown that metformin can also induce cell cycle arrest and induce cell apoptosis by inhibiting the expression of cyclin D1
metformin 21477 suppressor protein (Rb) [[56]]. In vivo studies have demonstrated the direct chemopreventive effect of metformin in the APCMin/+ mice, a mouse model of familial adenomatous polyposis [[29]]. In a different mouse model
metformin 21635 adenomatous polyposis [[29]]. In a different mouse model of colon carcinoma, it has been found that metformin is able to delay the onset of P53-dificient colon cancer in mice [[57]]. Moreover, metformin has been
metformin 21728 found that metformin is able to delay the onset of P53-dificient colon cancer in mice [[57]]. Moreover, metformin has been shown to suppress azoxymethane-induced formation of ACF, a reliable surrogate biomarker of
metformin 21983 activating AMPK [[30], [32]]. Other possible underlying mechanisms of the antineoplastic potential of metformin include its obesity antagonizing action [[58]], anti-inflammatory effect [[59]], and cancer stem cells
metformin 22163 effect [[59]], and cancer stem cells killing effect [[60]]. These data strongly support the notion that metformin is one of the promising candidates for cancer therapeutics. However, the underlying mechanisms are eagerly
metformin 22977 selection criteria and a systematic search of the literature. Furthermore, our meta-analysis suggested that metformin may play a significant role in CRC chemoprevention by acting at early stages of adenoma onset and advancement
metformin 23468 the selected studies were observational studies (cohort and case-control) in which the information on metformin use was obtained retrospectively. Observational studies have methodical shortcomings and are prone to
metformin 23960 unadjusted ORs, which may still influence the result and limiting comparability. The definitions of metformin use were different across the included studies, which may also lead to heterogeneity. Historical medical
metformin 24116 studies, which may also lead to heterogeneity. Historical medical data, such as exact dose and duration of metformin use, and other adjunctive therapies, were incomplete. Hence, neither dose-response nor duration-response
metformin 24251 therapies, were incomplete. Hence, neither dose-response nor duration-response association between metformin therapy and risk of CRA in T2D patients could be established. We could not obtain data about history
metformin 24483 tobacco smoke and alcohol consumption, which are strong risk factors for CRA [[62], [63]]. In this paper, metformin treatment was compared with thiazolidinediones, sulfonylureas, insulin, or other oral antidiabetic drugs,
metformin 24892 development of CRA [[64], [65]]. Therefore, it could be speculated that the observed useful activities of metformin might be an overestimation partially because of the adenoma-modifying activity resulted from other hypoglycemic
metformin 25082 resulted from other hypoglycemic drugs in the control group. Additionally, the conclusions regarding metformin therapy and the risk of advanced adenoma may be limited due to the inadequate sample size, and need
metformin 25601 meta-analysis.In conclusion, the results of this paper demonstrated that in T2D patients treatment with metformin is likely correlated with a significant decrease in both CRA risk and advanced adenoma risk. Considering
metformin 25739 significant decrease in both CRA risk and advanced adenoma risk. Considering the low side effect of metformin and the rising incidence rate of CRA, this study may provide significant public health implication for
metformin 26815 bowel adenoma*” OR “rectum neoplasm*” OR “rectum polyp*” OR “rectum adenoma*”) AND (“ metformin ” OR “dimethylbiguanidine” OR “dimethylguanylguanidine” OR “glucophage” OR “metformin
metformin 26916 (“metformin” OR “dimethylbiguanidine” OR “dimethylguanylguanidine” OR “glucophage” OR “ metformin hydrochloride” OR “hydrochloride, metformin” OR “metformin HCl” OR “HCl, metformin”).
metformin 26964 “dimethylguanylguanidine” OR “glucophage” OR “metformin hydrochloride” OR “hydrochloride, metformin ” OR “metformin HCl” OR “HCl, metformin”). Details of the search description for PubMed can
metformin 26983 “dimethylguanylguanidine” OR “glucophage” OR “metformin hydrochloride” OR “hydrochloride, metformin” OR “ metformin HCl” OR “HCl, metformin”). Details of the search description for PubMed can be found in Supplementary
metformin 27011 OR “metformin hydrochloride” OR “hydrochloride, metformin” OR “metformin HCl” OR “HCl, metformin ”). Details of the search description for PubMed can be found in Supplementary Table S2. The reference
metformin 28010 Eligible studies with the following criteria were included in this analysis: 1) the relationship between metformin therapy and CRA was evaluated; 2) metformin therapy was compared with non-metformin therapy; 3) OR or
metformin 28054 included in this analysis: 1) the relationship between metformin therapy and CRA was evaluated; 2) metformin therapy was compared with non-metformin therapy; 3) OR or RR with the corresponding 95% CIs reported
metformin 28094 relationship between metformin therapy and CRA was evaluated; 2) metformin therapy was compared with non- metformin therapy; 3) OR or RR with the corresponding 95% CIs reported or data were provided for their calculation;
metformin 28726 hypoglycemic drugs were compared with reference therapy or the risk of CRC was reported with the use of metformin were also excluded.Data extraction and quality assessmentCharacteristics of retrieved reports were extracted
Select Disease Character Offset Disease Term Instance
diabetes mellitus 5514 studies have suggested that CRC is correlated with several lifestyle diseases, including obesity and diabetes mellitus [[13]–[15]]. Thus, it has suggested that these conditions may be the targets for prevention of CRC.Globally,
hyperglycemia 19940 not yet completely clarified, insulin resistance, which results in subsequent hyperinsulinemia and hyperglycemia , is the most commonly proposed scenario, since insulin is able to promote mitosis through specific,
hyperinsulinemia 5708 targets for prevention of CRC.Globally, diabetes is a well-established, independent risk factor for CRC; hyperinsulinemia induced by insulin resistance has been considered as an importantly latent mechanism linking obesity,
hyperinsulinemia 19919 probably manifold and not yet completely clarified, insulin resistance, which results in subsequent hyperinsulinemia and hyperglycemia, is the most commonly proposed scenario, since insulin is able to promote mitosis
obesity 5502 growing body of studies have suggested that CRC is correlated with several lifestyle diseases, including obesity and diabetes mellitus [[13]–[15]]. Thus, it has suggested that these conditions may be the targets
obesity 5818 hyperinsulinemia induced by insulin resistance has been considered as an importantly latent mechanism linking obesity , immobile life and poor diet to CRC [[16]–[18]]. Encouragingly, several preclinical studies have shown
obesity 22005 [32]]. Other possible underlying mechanisms of the antineoplastic potential of metformin include its obesity antagonizing action [[58]], anti-inflammatory effect [[59]], and cancer stem cells killing effect [[60]].

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