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.

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 patients	Patients with CRC	Metformin user vs nonuser	HR: 0.81 (0.60-1.08)
Skinner et al[100], 2013	Retrospective cohort. 482 locally rectal cancer patients	Locally advanced rectal adenocarcinoma treated with chemoradiation and surgery	Metformin user vs nonuser	pCR: 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], 2016	Phase 2 Clinical trial. 50 refractory CRC patients	Refractory CRC patients	Metformin 850 mg twice a day+ 5-FU 425 mg/m2 weekly	PFS: 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 patients	Refractory CRC patients	Metformin 2500 mg a day+ Irinotecan 125 mg/m2 D1, D8, every 21 d	PFS: 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 patients	Stage III CRC patients	FOLFOX 4 12 cycles + metformin 500 mg 3 times a day	Neuropathy 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 gastrectomy	Metformin user vs nonuser	OS-HR: 0.58 (0.37-0.93). RFS-HR: 0.63 (0.41-0.98)
Lacroix et al[120], 2018	Retrospective Cohort. 371 Patients	Stage I to III GC patients	Metformin user vs nonuser	OS-HR: 0.73 (0.52-1.01); cancer specific mortality-HR: 0.86 (0.56-1.33)
Baglia et al[121], 2019	Prospective cohort study in Shangai. 543 GC patients	Breast, CRC, lung and GC patients	Metformin user vs nonuser	OS-HR: 1.11 (0.81-1.53). Disease-specific survival-HR: 1.03 (0.73-1.43)
Seo et al[119], 2019	Retrospective cohort study. 2187 GC resected patients: – 103 DM2 with metformin; –139 DM2 without metformin; –1945 non-diabetic	GC patients who underwent curative gastrectomy	Metformin user vs nonuser	HR: 0.45 (0.30-0.66)
PDAC
Sadeghi et al[128], 2012	Retrospective cohort. n = 302	DM2 patients. All stages. United States single center	Metformin user vs nonuser	HR: 0.64 (0.48-0.86)
Chaiteerakij et al[129], 2016	Retrospective cohort. n = 980	DM2 patients. All stages. United States single center	Metformin user vs nonuser	HR: 0.93 (0.81-1.07)
Lee et al[133], 2016	Retrospective cohort. n = 237	DM2 patients. All stages. Korean single center	Use of metformin ≥ 1-mo post-diagnosis vs nonuser	HR: 0.61 (0.46-0.81)
Ambe et al[130], 2016	Prospective cohort study n = 44	DM2 patients. Resected PDAC, stage I-II. United States single center	Metformin user vs nonuser	HR: 0.54 (0.16-1.86)
Cerullo et al[131], 2016	Retrospective cohort. n = 3393	Resected PDAC United States population based	Metformin use after surgery vs nonuser	HR: 0.79 (0.67-0.93)
Jang et al[132], 2017	Prospective cohort. n = 764	DM2, OHA user. Resected Korean population based	Metformin user vs nonuser	HR: 0.73 (0.61-0.87)
Hwang et al[135], 2013	Retrospective cohort. n = 516	DM2 patients. Locally advanced and metastatic. United Kingdom population based	Use of metformin peridiagnosis vs nonuser	HR: 1.11 (0.89-1.38)
Choi et al[134], 2016	Retrospective cohort. n = 183	DM2 patients. Locally advanced and metastatic. Korean single center	Metformin user vs nonuser	HR: 0.69 (0.49-0.97)
Kordes et al[137], 2015	RCT, n = 121	Locally advanced and metastatic. Multicentric. Netherlands	Gemcitabine-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 = 60	Metastatic. Single center. Italian	PEXG (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/d	HR: 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 PDAC	Metformin user vs nonuser	HR: 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 PDAC	Metformin user vs nonuser	HR: 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 PDAC	Metformin user vs nonuser	HR: 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 = 20	Locally advanced or metastatic. 2nd line treatment. Single center. Brazilian	Paclitaxel (80 mg/m2 D1, 8, 15 every 28 d) + metfomin 1750 mg/d	DCR at 8 wk 31, 6%
Pancreatic neuroendocrine tumor
Pusceddu et al[153], 2018	Retrospective cohort. n = 445	Locally advanced or metastatic. Multicentric. Italian	No DM2 vs DM2. Metformin user vs nonuser	HR: 0.45 (0.32-0.62). HR: 0.49 (0.34-0.69)
Hepatocellular carcinoma
Chen et al[163], 2011	Retrospective cohort. n = 53	DM2. Early-stage HCC. RFA treated. Single center. Taiwanese	Metformin user vs nonuser	HR: 0.24 (0.07-0.90)
Ma et al[164], 2016	Meta-analysis. 11 cohort studies. n = 3452	Studies that investigated metformin exposition. HCC patients	Metformin user vs nonuser	HR: 0.59 (0.42-0.83)
Intrahepatic cholangiocarcinoma
Yang et al[169], 2016	Retrospective cohort. n = 250	DM2. Newly diagnosed ICC. United States single center	Metformin user vs nonuser	HR: 0.80 (0.60-1.20)

PDAC: Pancreatic ductal adenocarcinoma; ORC: Origin recognition complex; HR: Hazard ratio; PCR: Polymerase chain reaction; OS: Overall survival; PFS: Progression-free survival; RFS: Regarding refeeding syndrome; OHA: Oxidized hyaluronate; RCT: Randomized clinical trial; PEXG: Pseudoexfoliative glaucoma; DCR: Dacryocystorhinostomy; HCC: Hepatocellular carcinoma; RAF: Rapidly accelerated fibrosarcoma; ICC: Intrahepatic cholangiocarcinoma; CRC: Colorectal cancer; DM2: Diabetes mellitus type 2; GC: Gastric cancer.