Meta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patients.

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metformin 46 Title: MedicineMeta-analysis of studies using metformin as a reducer for liver cancer risk in diabetic patientsShujuan MaYixiang ZhengYanni XiaoPengcheng ZhouHongzhuan
metformin 709 liver cancer risk in diabetic patients. This work was undertaken to better understand the effect of metformin use on liver cancer risk in diabetic patients.A comprehensive literature search was performed in PubMed,
metformin 1155 studies were included. Meta-analysis of 19 studies involving 550,882 diabetic subjects suggested that metformin use reduced the ratio of liver cancer by 48% (OR = 0.52; 95% CI, 0.40–0.68) compared with nonusers.
metformin 1484 hoc analyses of 2 randomized controlled trials found no significant difference between subjects with metformin and those without, with OR being 0.84 (95% CI, 0.10–6.83). After adjusting for hepatitis B/C virus
metformin 1791 stable, pooled OR ranged from 0.42 to 0.75.A protective effect for liver cancer was found in diabetic metformin users. However, more randomized clinical evidence is still needed to verify the results.Introduction1Liver
metformin 2687 insulin-dependent and insulin-independent mechanisms.[[4]] However, the evidence for a cancer preventive effect for metformin has not been consistently demonstrated.Association of metformin and risk of liver cancer are mainly
metformin 2751 for a cancer preventive effect for metformin has not been consistently demonstrated.Association of metformin and risk of liver cancer are mainly studied in animal and observational human studies. A meta-analysis
metformin 2882 cancer are mainly studied in animal and observational human studies. A meta-analysis demonstrated that metformin appeared to have a direct antihepatocellular carcinoma (HCC) effect in animal models.[[5]] Accumulating
metformin 3073 models.[[5]] Accumulating epidemiologic studies comparing the risk of liver cancer between those using metformin with those using other ADMs have shown somewhat variable results,[[6]–[9]] and it was also endorsed
metformin 3329 most studies.[[2]] Several meta-analyses have been published to determine if a consistent effect of metformin use on liver cancer incidence was evident.[[10]–[13]] Except for the incomplete included studies,
metformin 3750 differences in study designs, quality, population, the comparators used, estimation of the exposure to metformin (duration and dosage) and adjusted factors, as the inability to account for these factors may result
metformin 3929 account for these factors may result in certain degrees of bias. To better understand the association of metformin and risk of liver cancer, we embarked on a systematic review and meta-analysis with integrated overall,
metformin 4287 analyses of randomized controlled trials (RCTs) were included if they evaluated and defined exposure to metformin or biguanide, reported liver cancer incidence or related outcomes of diabetic patients, provided effective
metformin 5302 In order to include more potential literature, our overall search strategy only included terms for metformin and liver cancer. The comprehensive literature search was conducted as follow: ((liver cancer) OR (liver
metformin 5610 OR (HCC) OR (hepatic cancer) OR (hepatic neoplasm) OR (hepatic tumor) OR (cholangiocarcinoma)) AND (( metformin ) OR biguanide). We screened bibliographies of selected original studies, review articles, and relevant
metformin 6737 analysis on exposure used the dichotomous categorical variable of “with” or “without” use of metformin .Adjusted factors were extracted, and some of them were selected for further analysis: infected with
metformin 8287 calculate based on published methods.[[15]] OR was employed as a common measure of the association between metformin use and liver cancer risk due to the enrollment of case–control studies in most analyses. Between-study
metformin 9402 obesity, behavioral factors, use of statins, and time-related bias, given their modifying effects on metformin 's activity on DM and liver cancer risk.[[18]–[20]] Publication bias was detected for overall analysis
metformin 12274 analysis3.2On the basis of 19 studies[[6]–[9],[23]–[36]] involving 550,882 diabetic patients, compared with metformin nonusers, metformin use reduced the ratio of liver cancer by 48% (OR = 0.52; 95% CI, 0.40–0.68;
metformin 12294 studies[[6]–[9],[23]–[36]] involving 550,882 diabetic patients, compared with metformin nonusers, metformin use reduced the ratio of liver cancer by 48% (OR = 0.52; 95% CI, 0.40–0.68; P < .001), with
metformin 12953 (P = .069) and Egger test (P < .001).Figure 2Forest plot of the association between use of metformin and liver cancer risk in diabetic patients. RCT = randomized controlled trials. ∗Studies were
metformin 13476 controlled drugs, and adjustment did not change over the significant reduction in ratio of liver cancer in metformin users. Pooled result of post hoc analyses of 2 RCTs[[23]] found no significant difference between subjects
metformin 13598 Pooled result of post hoc analyses of 2 RCTs[[23]] found no significant difference between subjects with metformin and those without, with OR being 0.84 (95% CI, 0.10–6.83; P = .871) (Fig. 2). Subgroup analyses
metformin 13898 0.24–0.44) or studies with low quality (OR = 0.29; 95% CI, 0.18–0.49) showed an exaggeration in metformin 's effect. Metformin showed higher protective effect of liver cancer when compared with insulin (OR = 0.36;
metformin 14459 (OR = 0.57; 95% CI, 0.42–0.76; P < .001), numerical increases in the ratio of liver cancer in metformin users were found when the estimates were adjusted for HBV/HCV infection, cirrhosis, obesity, and behavioral
metformin 15402 14.0% to 39.5%).Discussion4This systematic review synthesized evidence on association between use of metformin and risk of liver cancer in diabetic patients from 23 studies. We used systematic strategy and broad
metformin 16037 meta-analysis of 19 studies involving 550,882 diabetic subjects found that, relative to nonuse, use of metformin reduced the ratio of liver cancer by 48% (OR = 0.52; 95% CI, 0.40–0.68; P < .001), with substantial
metformin 16695 86.1% to 33.7%) and population-based studies (I2 dropped from 89.2% to 7.3%). The beneficial effect of metformin was validated in observational studies, with a diminution in cohort studies (OR = 0.64) and a rise
metformin 17479 definition of exposure using dichotomous categorical variable of “with” or “without” use of metformin be somewhat less convincing. Thus we further subanalyzed supplemented comparisons between monotherapy
metformin 17620 Thus we further subanalyzed supplemented comparisons between monotherapy of ADMs. Results showed that metformin had higher protective effect of liver cancer when compared with insulin, other than sulfonylurea and
metformin 17866 plausible finding that use of insulin increased risk of liver cancer,[[44]] another explanation is that metformin is a first-line ADM prescribed in less severe or shorter duration of DM, while insulin is usually prescribed
metformin 18215 However, when compared to nonuser of any ADM (mild or newly diagnosed DM patients), monotherapy use of metformin achieved a 38% (OR = 0.62; 95% CI, 0.40–0.98) reduction in ratio of liver cancer, probably reflecting
metformin 18426 reflecting the real world scenario.Lots of confounders may have modifying effect on association between metformin and liver cancer risk in diabetic patients. Presence of DM in patients with cirrhosis is an independent
metformin 18600 patients with cirrhosis is an independent factor for the progression to liver cancer.[[50]] Moreover, metformin may be specifically sensitive to certain etiological types of liver cancer.[[10]] After adjusting for
metformin 18831 cirrhosis, obesity, and behavioral factors, the beneficial effects on the ratio of liver cancer for metformin use were significant and larger (pooled OR ranged from 0.42 to 0.51), which might be the true link between
metformin 18948 were significant and larger (pooled OR ranged from 0.42 to 0.51), which might be the true link between metformin use and liver cancer risk in diabetic patients. Recent reviews underscored the prevalence of time-related
metformin 19140 prevalence of time-related bias in observational studies, potentially leading to inflated estimates of metformin 's protective effect.[[19]] Time-related bias includes immortal-time bias, time-window bias, and time-lag
metformin 19941 reduction (OR = 0.75; 95% CI, 0.68–0.83; P < .001), which might suggest a synergistic effect of metformin and statins for liver cancer, in addition to their dose-dependent protective effects.[[46],[52]] Given
metformin 20209 chemo-preventive strategy is necessary, especially for cheap nonetiology-specific medications, like metformin and statins, still with favorable safety profile.[[52]] However, further researches are needed to establish
metformin 20346 favorable safety profile.[[52]] However, further researches are needed to establish definitive role of metformin and statins on the prevention of liver cancer in diabetic patients.The observational nature allows only
metformin 20548 allows only an association to be established. Plenty of experimental studies have added evidence to metformin 's protective effect on malignancies. Although the exact mechanism is not fully understood, several biologically
metformin 20707 exact mechanism is not fully understood, several biologically plausible mechanisms have shown that metformin might have direct antiliver cancer activity by inhibiting proliferation and colony formation ability
metformin 21297 tumor growth in mouse models.[[56]] Moreover, as an antihyperglycemic agent and insulin sensitizer, metformin treatment inhibits hepatic gluconeogenesis,[[57]] reduces serum concentrations of insulin and insulin
metformin 22645 confounders were failed to control, such as information like details of DM (severity and duration) and metformin use (dose and duration) were absent in most studies, which would have been important to adjust for residual
metformin 23112 studies.[[60]]Conclusion5In conclusion, a protective effect in the risk of liver cancer was found in diabetic metformin users, and the protective effect was validated in most of our exploratory analyses. However, the conclusion
Select Disease Character Offset Disease Term Instance
obesity 1617 OR being 0.84 (95% CI, 0.10–6.83). After adjusting for hepatitis B/C virus infection, cirrhosis, obesity , behavioral factors, and time-related bias, the association was stable, pooled OR ranged from 0.42 to
obesity 6910 for further analysis: infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), cirrhosis, obesity (including body mass index and obesity), behavioral factors (including alcohol abuse and cigarette smoking),
obesity 6949 hepatitis B virus (HBV) or hepatitis C virus (HCV), cirrhosis, obesity (including body mass index and obesity ), behavioral factors (including alcohol abuse and cigarette smoking), use of statins, and time-related
obesity 9301 Analyses of adjusted estimates were emphasized on studies controlling for HBV/HCV infection, cirrhosis, obesity , behavioral factors, use of statins, and time-related bias, given their modifying effects on metformin's
obesity 11852 to age and sex, most studies adjusted for HBV/HCV infection,[[7],[24],[25],[27],[30],[32],[33],[40]] obesity ,[[7],[25],[31],[32]] behavioral factors,[[8],[24],[25],[31]–[33]] use of statins,[[6],[31],[38]] and
obesity 14553 cancer in metformin users were found when the estimates were adjusted for HBV/HCV infection, cirrhosis, obesity , and behavioral factors (pooled ORs ranged from 0.42 to 0.51), while the ratio reduction decreased in
obesity 18742 certain etiological types of liver cancer.[[10]] After adjusting for HBV/HCV infection, cirrhosis, obesity , and behavioral factors, the beneficial effects on the ratio of liver cancer for metformin use were

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