Repurposing metformin for the treatment of gastrointestinal cancer

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 groups	Risk estimates and 95%CI
Colorectal cancer
Cardel et al[82], 2014	Case-control study. Cases-controls: 2088:9060	Cases: DM2 with CRC. Controls: DM2 without CRC	Metformin user vs nonuser	OR: 0.83 (0.68-1.00)
Lee et al[83], 2011	Prospective Cohort, Taiwan. n = 480984	DM2 and cancer free subjects	Metformin user vs nonuser	HR: 0.36 (0.13-0.98)
Sehdev et al[84], 2015	Case control study. Cases-controls: 2682:5365	Cases: DM2 with CRC. Controls: DM2 without CRC	Metformin user vs nonuser	OR: 0.85 (0.76-0.95)
Tseng et al[84]., 2012	Retrospective Cohort. Men: 493704. Women: 502139	Subjects covered by National Health Insurance without CRC	Metformin user vs nonuser	RR: 0.64 (0.49-0.84)
Zhang et al[86], 2011	Meta-analysis. 108161 DM2 patients	Studies conducted in humans that evaluate metformin and CRC	Metformin user vs nonuser	RR: 0.63 (0.47-0.84)
Kowall et al[87], 2015	Retrospective Cohort, United Kingdom. 80263 DM2 patients	Patients aged 30-89 years with DM2 diagnosis	Metformin user vs sulfonylurea user	HR: 1.04 (0.82-1.31)
Lin et al[88], 2015	Prospective Cohort. 36270 DM2 patients. 145080 non DM2	Patients older than 20 years old DM2 and Cancer- free	Metformin user vs nonuser	HR: 0.74 (0.53-1.03)
Smiechowski et al[89], 2013	Case-control, United Kingdom. Cases-controls: 607:5837	DM patients treated with non-insulin antidiabetic agents	Metformin user vs nonuser	RR: 0.93 (0.73-1.18)
Bodmer et al[90], 2012	Case control, United Kingdom. Cases-controls: 920:5519	Cases: DM2 with CRC. Controls: DM2 without CRC	Metformin user vs nonuser	Men: 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 group	Biguanide user vs non-diabetic	HR: 1.19 (1.08-1.30)
Bradley et al[92], 2018	Retrospective Cohort, Northern California. 47351 DM2 patients	DM2 and no history of cancer or metformin use	Long-term metformin use ( 5 years) vs nonuser	All 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 studies	Studies about metformin therapy and risk of adenoma/CRC in DM2 patients	Metformin user vs nonuser	Adenoma: 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 endoscopy	Metformin 250 daily or placebo (1:1) for 1 yr	Adenoma: RR 0.60 (0.39-0.92)
Gastric cancer
Tseng et al[107], 2016	Retrospective Cohort, Taiwan. 287971 DM2 with metformin. 16217 DM2 without metformin	DM2 patients newly treated with antidiabetic drugs	Metformin user vs nonuser	HR: 0.45 (0.36-0.56)
Dulskas et al[108], 2020	Retrospective Cohort study. n = 99992	DM2 patients with gastric cancer	Metformin user vs nonuser	SIR: 0.75 (0.66-0.86)
Ruiter et al[109], 2012	Retrospective Cohort study. 85289 DM2 patients	DM2 with more than one prescription of antidiabetic drugs	Metformin user vs sulfonylurea user	HR: 0.90 (0.88-0.91)
Kim et al[110], 2014	Retrospective cohort study. 39978 DM2 patients	DM2 receiving oral antidiabetic drugs	Metformin user and non-insulin user vs nonuser	HR: 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 GC	Metformin user vs nonuser	HR: 0.49 (0.24-0.98)
Tsilidis et al[113], 2014	Retrospective Cohort study. 51484 metformin. 18264 sulfonylureas	DM2 receiving oral antidiabetic drugs	Metformin user vs sulfonylurea user	HR: 0.96 (0.60-1.56)
de Jong et al[114], 2017	Retrospective Cohort study, Netherlands. 57621 DM2 with OHA	DM2 receiving oral antidiabetic drugs	Metformin user vs nonuser	HR: 0.97 (0.82-1.15)
Zheng et al[115], 2019	Prospective Cohort study. 544130 DM2 patients	Diabetes Cohort: DM2 receiving antidiabetic drugs. Matched cohort: common-medication users. Exclusion: History of GC or gastrectomy	Metformin user vs nonuser	Non-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 studies	Studies conducted in humans that evaluate metformin and GC risk	Metformin user vs nonuser	HR: 0.79 (0.62-1.00)
Zhou et al[117], 2017	Meta-analysis. 7 Cohort studies. n = 591077	Studies conducted in humans that evaluate metformin and GC risk	Metformin user vs nonuser	HR: 0.76 (0.64-0.91)
Pancreatic ductal adenocarcinoma
Currie et al[123], 2009	Retrospective cohort study. n = 62.809 DM2. Comparison between treatment: Metformin alone; Sulfonylurea alone; metformin plus sulfonylurea; insulin	DM2 developed > 40 years of age; United Kingdom residents	Metformin vs Sulfonylurea. Metformin vs Insulin	HR: 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; insulin	DM subjects; cases: Newly PDAC diagnosed. Controls: Nonblood relative controls; United States residents	Metformin user vs nonuser	OR: 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 cases	DM2 patients exposed to metformin alone or combined to sulfonylurea	Metformin user vs nonuser	RR: 0.38 (0.14-0.91)
Zhang et al[125], 2013	Meta-analysis of 37 case-control and cohort studies. n = 1535636	DM2 patients on treatment	Metformin user vs nonuser	SRR: 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 insulin	OR: 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 controls	Metformin user vs nonuser	OR: 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 = 550.882	DM2 exposed to metformin or biguanide	Metformin user vs nonuser	OR: 0.52 (0.40-0.68)
Intrahepatic cholangiocarcinoma
Chaiteerakij et al[168], 2013	Clinic-hospital based case-control. Cases-controls: 612:594	Cases: ICC patients. Controls: Non-cancer patients	Metformin user vs nonuser	OR: 0.40 (0.20-0.90)

PDAC: Pancreatic ductal adenocarcinoma; HR: Hazard ratio; OHA: Oxidized hyaluronate; RCT: Randomized clinical trial; HCC: Hepatocellular carcinoma; ICC: Intrahepatic cholangiocarcinoma; CRC: Colorectal cancer.