Review
Copyright ©The Author(s) 2021.
World J Gastroenterol. May 7, 2021; 27(17): 1883-1904
Published online May 7, 2021. doi: 10.3748/wjg.v27.i17.1883
Table 1 Selected clinical studies of metformin on digestive system cancers chemoprevention
Ref.
Study design and population
Inclusion criteria
Combined interventions /drugs
Main findings
Comparison groupsRisk estimates and 95%CI
Colorectal cancer
Cardel et al[82], 2014Case-control study. Cases-controls: 2088:9060Cases: DM2 with CRC. Controls: DM2 without CRCMetformin user vs nonuserOR: 0.83 (0.68-1.00)
Lee et al[83], 2011 Prospective Cohort, Taiwan. n = 480984DM2 and cancer free subjectsMetformin user vs nonuserHR: 0.36 (0.13-0.98)
Sehdev et al[84], 2015 Case control study. Cases-controls: 2682:5365Cases: DM2 with CRC. Controls: DM2 without CRCMetformin user vs nonuser OR: 0.85 (0.76-0.95)
Tseng et al[84]., 2012 Retrospective Cohort. Men: 493704. Women: 502139Subjects covered by National Health Insurance without CRCMetformin user vs nonuserRR: 0.64 (0.49-0.84)
Zhang et al[86], 2011Meta-analysis. 108161 DM2 patientsStudies conducted in humans that evaluate metformin and CRCMetformin user vs nonuserRR: 0.63 (0.47-0.84)
Kowall et al[87], 2015Retrospective Cohort, United Kingdom. 80263 DM2 patientsPatients aged 30-89 years with DM2 diagnosisMetformin user vs sulfonylurea userHR: 1.04 (0.82-1.31)
Lin et al[88], 2015 Prospective Cohort. 36270 DM2 patients. 145080 non DM2Patients older than 20 years old DM2 and Cancer- free Metformin user vs nonuserHR: 0.74 (0.53-1.03)
Smiechowski et al[89], 2013 Case-control, United Kingdom. Cases-controls: 607:5837DM patients treated with non-insulin antidiabetic agentsMetformin user vs nonuserRR: 0.93 (0.73-1.18)
Bodmer et al[90], 2012 Case control, United Kingdom. Cases-controls: 920:5519Cases: DM2 with CRC. Controls: DM2 without CRCMetformin user vs nonuserMen: OR: 1.81 (1.25-2.62). Women: OR: 1.00 (0.63-1.58)
Knapen et al[91], 2013 Retrospective Cohort, Denmark. 177281 DM2 with OHA Oral antidiabetic drug users were matched 1:3 with population-based reference groupBiguanide user vs non-diabeticHR: 1.19 (1.08-1.30)
Bradley et al[92], 2018 Retrospective Cohort, Northern California. 47351 DM2 patientsDM2 and no history of cancer or metformin useLong-term metformin use ( 5 years) vs nonuserAll population: HR: 0.78 (0.60-1.02). Men: HR: 0.65 (0.45-0.94)
Liu et al[175], 2017 Meta-analysis. 20 case-control and cohort studiesStudies about metformin therapy and risk of adenoma/CRC in DM2 patientsMetformin user vs nonuserAdenoma: OR: 0.75 (0.59-0.97). Carcinoma: OR: 0.781 (0.7-0.87)
Higurashi et al[94], 2016 RCT, phase 3. n = 151 patients with resected adenomas or polyps Non- diabetic adult patients who had previously had single or multiple colorectal adenomas or polyps resected by endoscopyMetformin 250 daily or placebo (1:1) for 1 yrAdenoma: RR 0.60 (0.39-0.92)
Gastric cancer
Tseng et al[107], 2016 Retrospective Cohort, Taiwan. 287971 DM2 with metformin. 16217 DM2 without metforminDM2 patients newly treated with antidiabetic drugsMetformin user vs nonuser HR: 0.45 (0.36-0.56)
Dulskas et al[108], 2020 Retrospective Cohort study. n = 99992DM2 patients with gastric cancerMetformin user vs nonuser SIR: 0.75 (0.66-0.86)
Ruiter et al[109], 2012 Retrospective Cohort study. 85289 DM2 patientsDM2 with more than one prescription of antidiabetic drugsMetformin user vs sulfonylurea userHR: 0.90 (0.88-0.91)
Kim et al[110], 2014 Retrospective cohort study. 39978 DM2 patientsDM2 receiving oral antidiabetic drugsMetformin user and non-insulin user vs nonuserHR: 0.73 (0.53-1.01)
Cheung et al[112], 2019 Prospective Cohort study. 7266 DM2 DM2 with prescription of therapy for H. pylori. Exclusion: history of GCMetformin user vs nonuserHR: 0.49 (0.24-0.98)
Tsilidis et al[113], 2014 Retrospective Cohort study. 51484 metformin. 18264 sulfonylureas DM2 receiving oral antidiabetic drugsMetformin user vs sulfonylurea userHR: 0.96 (0.60-1.56)
de Jong et al[114], 2017 Retrospective Cohort study, Netherlands. 57621 DM2 with OHADM2 receiving oral antidiabetic drugsMetformin user vs nonuserHR: 0.97 (0.82-1.15)
Zheng et al[115], 2019Prospective Cohort study. 544130 DM2 patientsDiabetes Cohort: DM2 receiving antidiabetic drugs. Matched cohort: common-medication users. Exclusion: History of GC or gastrectomyMetformin user vs nonuserNon-cardia: HR: 0.93 (0.78-1.12). Cardia: HR: 1.49 (1.09-2.02)
Shuai et al[116], 2020 Meta-analysis. 11 cohort studiesStudies conducted in humans that evaluate metformin and GC riskMetformin user vs nonuserHR: 0.79 (0.62-1.00)
Zhou et al[117], 2017 Meta-analysis. 7 Cohort studies. n = 591077Studies conducted in humans that evaluate metformin and GC riskMetformin user vs nonuserHR: 0.76 (0.64-0.91)
Pancreatic ductal adenocarcinoma
Currie et al[123], 2009Retrospective cohort study. n = 62.809 DM2. Comparison between treatment: Metformin alone; Sulfonylurea alone; metformin plus sulfonylurea; insulinDM2 developed > 40 years of age; United Kingdom residentsMetformin vs Sulfonylurea. Metformin vs InsulinHR: 0.20 (0.11-0.36). HR: 0.22 (0.12-0.38)
Li et al[124], 2009 Hospital-based case control. Cases-controls: 973:863. Comparison between treatment: Metformin; insulin secretagogues; Other antidiabetic medications; insulinDM subjects; cases: Newly PDAC diagnosed. Controls: Nonblood relative controls; United States residentsMetformin user vs nonuserOR: 0.38 (0.22-0.69)
Soranna et al[126], 2012 Meta-analysis of 17 case-control and cohort studies. Any cancer: 17 case-control and cohort studies; 37632 cases. PDAC: 4 case-controls and retrospective cohort studies; 1192 casesDM2 patients exposed to metformin alone or combined to sulfonylureaMetformin user vs nonuserRR: 0.38 (0.14-0.91)
Zhang et al[125], 2013 Meta-analysis of 37 case-control and cohort studies. n = 1535636DM2 patients on treatment Metformin user vs nonuserSRR: 0.54 (0.35-0.83)
Hepatocellular carcinoma
Donadon et al[159], 2010 Clinic-hospitalbased case control. Cases-controls: 190:359 Cases: HCC patients. Controls: Liver cirrhosis patients and healthy controls Metformin vs sulfonylurea. Metformin vs insulinOR: 0.39 (0.22-0.73). OR: 0.21 (0.11-0.42)
Hassan et al[158], 2010 Hospital-based case control. Cases-controls: 122:86 Cases: HCC. Controls: Healthy controlsMetformin user vs nonuserOR: 0.30 (0.20-0.60)
Ma et al[160], 2017 Meta-analysis of 19 case-control and cohort studies and post hoc analysis of RCT of DM2 patients. n = 550.882DM2 exposed to metformin or biguanide Metformin user vs nonuserOR: 0.52 (0.40-0.68)
Intrahepatic cholangiocarcinoma
Chaiteerakij et al[168], 2013 Clinic-hospital based case-control. Cases-controls: 612:594Cases: ICC patients. Controls: Non-cancer patientsMetformin user vs nonuserOR: 0.40 (0.20-0.90)
Table 2 Selected clinical studies of metformin on digestive system cancers treatment
Ref.
Study design and population
Inclusion criteria
Combined interventions /drugs
Main findings
Colorectal cancer
Ramjeesingh et al[99], 2016 Retrospective cohort. 1394 all stages CRC patientsPatients with CRC Metformin user vs nonuserHR: 0.81 (0.60-1.08)
Skinner et al[100], 2013Retrospective cohort. 482 locally rectal cancer patientsLocally advanced rectal adenocarcinoma treated with chemoradiation and surgeryMetformin user vs nonuserpCR: OR: 16.8 (1.6-181.1). OS at 5 and 10 years (metformin vs non): 81% and 79% vs 56% and 39% (P = 0.022)
Miranda et al[101], 2016Phase 2 Clinical trial. 50 refractory CRC patientsRefractory CRC patientsMetformin 850 mg twice a day+ 5-FU 425 mg/m2 weeklyPFS: 1.8 mo. OS: 7.9 mo. Obese vs lean: 12.4 vs 5.8 mo
Bragagnoli et al[102], 2021 Phase 2 Clinical trial, 41 refractory CRC patientsRefractory CRC patientsMetformin 2500 mg a day+ Irinotecan 125 mg/m2 D1, D8, every 21 dPFS: 2.4 mo, CI 95%, 2.0-4.5 mo. OS: 8.4 mo, CI 95%, 5.9-10.8 mo
El-Fatatry et al[103], 2018 Clinical Trial, 40 Stage III CRC patientsStage III CRC patientsFOLFOX 4 12 cycles + metformin 500 mg 3 times a dayNeuropathy grade 2-3 (metformin vs non): 60% vs 95% (P = 0.009)
Gastric cancer
Lee et al[118], 2016 Retrospective Cohort, single center in Korea. 1974 GC resected patients: – 132 DM2 with metformin; –192 DM2 without metformin; –1648 non-diabetic GC patients who underwent curative gastrectomyMetformin user vs nonuserOS-HR: 0.58 (0.37-0.93). RFS-HR: 0.63 (0.41-0.98)
Lacroix et al[120], 2018 Retrospective Cohort. 371 PatientsStage I to III GC patientsMetformin user vs nonuserOS-HR: 0.73 (0.52-1.01); cancer specific mortality-HR: 0.86 (0.56-1.33)
Baglia et al[121], 2019Prospective cohort study in Shangai. 543 GC patients Breast, CRC, lung and GC patientsMetformin user vs nonuserOS-HR: 1.11 (0.81-1.53). Disease-specific survival-HR: 1.03 (0.73-1.43)
Seo et al[119], 2019Retrospective cohort study. 2187 GC resected patients: – 103 DM2 with metformin; –139 DM2 without metformin; –1945 non-diabeticGC patients who underwent curative gastrectomyMetformin user vs nonuserHR: 0.45 (0.30-0.66)
PDAC
Sadeghi et al[128], 2012 Retrospective cohort. n = 302DM2 patients. All stages. United States single centerMetformin user vs nonuserHR: 0.64 (0.48-0.86)
Chaiteerakij et al[129], 2016 Retrospective cohort. n = 980DM2 patients. All stages. United States single centerMetformin user vs nonuserHR: 0.93 (0.81-1.07)
Lee et al[133], 2016 Retrospective cohort. n = 237DM2 patients. All stages. Korean single centerUse of metformin ≥ 1-mo post-diagnosis vs nonuserHR: 0.61 (0.46-0.81)
Ambe et al[130], 2016 Prospective cohort study n = 44DM2 patients. Resected PDAC, stage I-II. United States single centerMetformin user vs nonuserHR: 0.54 (0.16-1.86)
Cerullo et al[131], 2016 Retrospective cohort. n = 3393Resected PDAC United States population basedMetformin use after surgery vs nonuserHR: 0.79 (0.67-0.93)
Jang et al[132], 2017 Prospective cohort. n = 764DM2, OHA user. Resected Korean population basedMetformin user vs nonuserHR: 0.73 (0.61-0.87)
Hwang et al[135], 2013 Retrospective cohort. n = 516DM2 patients. Locally advanced and metastatic. United Kingdom population basedUse of metformin peridiagnosis vs nonuserHR: 1.11 (0.89-1.38)
Choi et al[134], 2016 Retrospective cohort. n = 183DM2 patients. Locally advanced and metastatic. Korean single centerMetformin user vs nonuserHR: 0.69 (0.49-0.97)
Kordes et al[137], 2015RCT, n = 121Locally advanced and metastatic. Multicentric. NetherlandsGemcitabine-everolimus (1000 mg/m2 D1, 8, 15-every 28 d-1.000 mg/d) +/- metformin (2000 mg/d)HR: 1.05 (0.72-1.55)
Reni et al[138], 2016 RCT. n = 60Metastatic. Single center. ItalianPEXG (cisplatin-epirubicin-capecitabine-gemcitabine: 30 mg/m2 D1,14- 30 mg/m2 D1,14-2500 mg/m2 D1–28 – 800 mg/m2 D1–14) +/- metformin 2000 mg/dHR: 1.56 (0.87-2.80)
Zhou et al[136], 2017 Meta-analysis12 cohort studies and 2 RCT. n = 94778 Studies that investigated metformin exposition. All stages PDACMetformin user vs nonuserHR: 0.77 (0.68-0.87)
Li et al[139], 2017 Meta-analysis. 9 cohort study and 2 RCT. n = 8089 Studies that investigated metformin exposition. All stages PDACMetformin user vs nonuserHR: 0.86 (0.76-0.97)
Wan et al[140], 2018 Meta-analysis 15 cohort studies and 2 RCT, n = 36791 Studies that investigated metformin exposition. All stages PDACMetformin user vs nonuserHR: 0.88 (0.80-0.97). Asians only HR: 0.74 (0.58-0.94); Stage I-II HR: 0.76 (0.68-0.86); Stage III-IV HR: 1.08 (0.82-1.43)
Braghiroli et al[141], 2015 Single-arm phase II. n = 20Locally advanced or metastatic. 2nd line treatment. Single center. BrazilianPaclitaxel (80 mg/m2 D1, 8, 15 every 28 d) + metfomin 1750 mg/dDCR at 8 wk 31, 6%
Pancreatic neuroendocrine tumor
Pusceddu et al[153], 2018 Retrospective cohort. n = 445Locally advanced or metastatic. Multicentric. Italian No DM2 vs DM2. Metformin user vs nonuserHR: 0.45 (0.32-0.62). HR: 0.49 (0.34-0.69)
Hepatocellular carcinoma
Chen et al[163], 2011 Retrospective cohort. n = 53DM2. Early-stage HCC. RFA treated. Single center. Taiwanese Metformin user vs nonuserHR: 0.24 (0.07-0.90)
Ma et al[164], 2016Meta-analysis. 11 cohort studies. n = 3452 Studies that investigated metformin exposition. HCC patientsMetformin user vs nonuserHR: 0.59 (0.42-0.83)
Intrahepatic cholangiocarcinoma
Yang et al[169], 2016 Retrospective cohort. n = 250DM2. Newly diagnosed ICC. United States single centerMetformin user vs nonuserHR: 0.80 (0.60-1.20)