The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances

Figures & data

Figure 1 Molecular structure of metformin.

Table 1 A summary of clinical studies of metformin effects on cancers

Study	Number of Patients	Year	Intervention	Outcome	Cancer Type
Taiwan National Health Insurance Data Survey Lee MS et al^Citation71	Total: 12,005 Patients using metformin: 4,597	2011	Drug: metformin (orally)	Metformin reduces the chance of cancers up to 88%	Various
Decensi et al^Citation72	Total: 4,042 cancer events and 529 cancer deaths	2010	Drug: metformin (orally)	Likelihood of developing cancers in patients using metformin is 30% lower than that of patients taking other drugs	Various
Bowker et al^Citation90	1,000	2006	Drug: metformin, sulfonylurea and insulin	Incidence of death of medications users: 3.5, 4.9 and 8.8 respectively	Various
Landman et al^Citation73	1,353	2010	Drug: metformin	Mortality was lower in patients taking metformin	Various
Currie et al^Citation74	60,000	2009	Drug: metformin, sulfonylurea and insulin	Patients who use insulin or other similar drugs compared to metformin users are more likely to have solid cancers in future	Colon, pancreas, breast and prostate
Soranna et al^Citation75	Not provided	2012	Drug: metformin and sulfonylurea	Metformin, but not sulfonylurea, appears to reduce subsequent cancer risk	Various
Noto et al^Citation76	Patients using metformin: 21,195 Cases of death from cancer in these patients: 991	2012	Drug: metformin	The use of metformin in diabetic patients was associated with significantly lower risks of cancer mortality and incidence	Various
Libby et al^Citation88	8,000	2009	Drug: metformin	Cancer was diagnosed in 7.3% of metformin users compared with 11.6% of non-users	Various
Higurashi et al^Citation77	498	2016	Drug: metformin	Low-dose metformin reduced the prevalence and number of metachronous adenomas or polyps after polypectomy and metformin has a potential role in the chemoprevention of colorectal cancer	Colorectal adenoma or polyps
Joshua et al^Citation78	24	2014	Drug: metformin	Neoadjuvant metformin is well tolerated prior to radical prostatectomy and data to date indicate promising effects on metabolic and tissue proliferation and signalling parameters	Prostate cancer
Campagnoli et al^Citation79	125	2012	Drug: metformin	Using of metformin reduced the level of testosterone and insulin and its destructive effects, such as insulin resistance	Breast cancer
Evans et al^Citation92	Not provided	2005	Drug: metformin	Using metformin decreased cancer incidence	Various
Monami et al^Citation80	195	2009	Drug: metformin and sulfonylurea	Exposure to metformin for more than 36 months was associated with a significant reduction in the risk of cancer	Various
Home et al^Citation81	105	2010	Drug: metformin, rosiglitazone and glibenclamide	No difference in cancer incidence between patients treated with metformin and patients treated with rosiglitazone	Various
Baur et al^Citation82	7,000	2010	Drug: metformin and insulin	Patients on metformin had a lower prevalence of malignancies, comparable with that among nondiabetic patients	Various
Li D et al^Citation82	973	2009	Drug: insulin, insulin secretagogues, metformin, and other antidiabetic medications	Metformin use was associated with reduced risk, and insulin or insulin secretagogue use was associated with increased risk of pancreatic cancer in diabetic patients.	Pancreatic cancer
Berstein et al^Citation84	90	2010	Drug: metformin, sulfonylurea and insulin	Better treatment in women who were treated with metformin compare with sulfonylurea or insulin	Breast cance
Rieken et al^Citation85	Total: 6,863 Patients with T2DM on metformin: 287 Patients with T2DM on other antidiabetic medications: 377	2014	Drug: metformin	Better RFS in patients treated with radical prostatectomy for prostate cancer	Prostate cancer
Spratt et al^Citation86	Total: 2901 patients 157 on metformin 162 diabetic non-metformin 2,582 nondiabetic	2013	Drug: metformin	Using metformin may improve patients’ PSA, RFS, OS, and reduce the development chance of prostate cancer	Prostate cancer
Margel et al^Citation87	3,837	2013	Drug: metformin	Using metformin decreases both likelihood of relapse and mortality	Prostate cancer

Table 2 A summary of clinical trials studies of metformin effects on cancers

Study	NCT Number	Status	Participants	Period	Intervention	Cancer Type	Outcome
A Phase III randomized trial of metformin vs placebo in early stage breast cancer	NCT01101438 (L https://clinicaltrials.gov/ct2/show/NCT01101438?term=NCT01101438&rank=1 ink)	Active	3,582 (original estimated enrollment) 18 years to 74 years (adult, older adult) All sex	April 9, 2010 to February 2022 (Estimated Primary Completion Date)	Drug: metformin (twice a day for 5 years after diagnosis, given orally) Other: placebo (given orally)	Breast cancer	Metformin improved patients’ PFS
A randomized Phase II study of chemotherapy ± metformin in metastatic pancreatic cancer	NCT01167738 (Link)  https://clinicaltrials.gov/ct2/show/NCT01167738?term=NCT01167738&rank=1	Terminated	82 (original estimated enrollment) 18 years to 75 years (adult, older adult) All sex	July 21, 2010 to December 2014	Drug: capecitabine, cisplatinum, epirubicine, gemcitabine and metformin	Pancreatic cancer	Metformin improved patients’ PFS with combination of chemotherapy compared to combined chemotherapy alone
A Phase II, randomized, placebo controlled study to evaluate the efficacy of the combination of gemcitabine, erlotinib and metformin in patients with locally advanced and metastatic pancreatic cancer	NCT01210911 (Link)  https://clinicaltrials.gov/ct2/show/NCT01210911?term=NCT01210911&rank=1	Completed	120 18 years to 80 years (adult, older adult) All sex	September 28, 2010 to February 2014	Drug: gemcitabine, erlotinib, metformin and placebo	Pancreatic cancer	Metformin improved patients’ PFS
Prospective study of metformin in castration-resistant prostate cancer	NCT01215032 (Link)  https://clinicaltrials.gov/ct2/show/NCT01215032?term=NCT01215032&rank=1	Terminated	106 (original estimated enrollment) Child, adult, older adult Male	October 4, 2010 to January 2015	Drug: metformin (taken orally twice daily each 28-day cycle, for 12 cycles)	Prostate cancer	Metformin improved patients’ PSA
A Phase II single arm study to examine the effects of metformin on cancer metabolism in patients with early stage breast cancer receiving neoadjuvant chemotherapy	NCT01266486 (Link)  https://clinicaltrials.gov/ct2/show/NCT01266486?term=NCT01266486&rank=1	Completed	41 18 years and older (adult, older adult) All sex	December 23, 2010 to May 2014	Drug: metformin (extended release metformin 1,500 mg once daily for 14–21 days)	Breast cancer	Metformin activates AMPK and reduces the levels of 4E-BPs and S6Ks
A randomized Phase II, double blind trial of standard chemotherapy with metformin (vs placebo) in women with metastatic breast cancer receiving first, second, third or fourth line chemotherapy with anthracycline, taxane, platinum, capecitabine or vinorelbine based regimens	NCT01310231 (Link)  https://clinicaltrials.gov/ct2/show/NCT01310231?term=NCT01310231&rank=1	Completed	40 18 years to 75 years (adult, older adult) Female	February 18, 2011 to July 14, 2016	Drug: metformin (metformin 850 mg bid in addition to standard chemotherapy) Other: placebo (placebo bid in addition to standard chemotherapy)	Metastatic breast cancer	Metformin improved patients’ overall response rate (ORR)
Phase II study evaluating the efficacy of the combination of metformin to neoadjuvant radiochemotherapy in the treatment of locally advanced rectal cancer	NCT02437656 (Link)  https://clinicaltrials.gov/ct2/show/NCT02437656?term=NCT02437656&rank=1	Completed	60 18 years and older (adult, older adult) All Sex	May 5, 2015 to March 2017	Drug: metformin (850 mg 2 times/day and 850 mg 3 times/day)	Rectal cancer	Metformin improved patients’ sphincter preservation rate (SPR)
Clinical and biologic effects of metformin in early stage breast cancer	NCT00897884 (Link)  https://clinicaltrials.gov/ct2/show/NCT00897884?term=NCT00897884&rank=1	Completed	40 18 years to 70 years (adult, older adult) Female	May 8, 2009 to July 2011	Drug: metformin (500 mg tablet, taken 3 times a day for 2–3 weeks)	Breast cancer	Metformin can reduces cell proliferation rates in tumor tissue
A Phase I trial of lapatinib in combination with 1) sirolimus or 2) metformin in advanced cancer	NCT01087983 (Link)  https://clinicaltrials.gov/ct2/show/NCT01087983?term=NCT01087983&rank=1	Completed	118 Child, adult, older adult All sex	March 15, 2010 to September 2015	Drug: lapatinib (starting oral dose of 500 mg daily for 21) Drug: sirolimus (starting oral dose 1 mg daily) Drug: metformin (starting oral dose 1,000 mg daily)	Advanced cancers	Lapatinib when used in combination with metformin will have beneficial effects in advanced cancer
Pre-surgical trial of metformin in patients with operable breast cancer	NCT00984490 (Link)  https://clinicaltrials.gov/ct2/show/NCT00984490?term=NCT00984490&rank=1	Terminated	30 (original estimated enrollment) 18 years and older (adult, older adult) Not provided	September 24, 2009 to July 2010	Drug: metformin (metformin: 850 mg orally twice daily for 7–21 days, discontinued 24–36 h prior to surgery) Other: laboratory biomarker analysis (blood and tissue collection to determine the in situ biologic effect of metformin)	Breast cancer	Metformin changes proliferation (Ki67) and apoptosis before and after treatment in women with operable stage I or II breast cancer
APhase II evaluation of metformin, targeting cancer stem cells for the prevention of relapse in patients with stage IIC/III/IV ovarian, fallopian tube, and primary peritoneal cancer	NCT01579812 (Link)  https://clinicaltrials.gov/ct2/show/NCT01579812?term=NCT01579812&rank=1	Completed	90 19 years to 79 years (adult, older adult) Female	March 30, 2012 to June 2017	Drug: metformin	Ovarian, fallopian tube, and primary peritoneal cancer	Metformin improved patients’ RFS
APhase II study of metformin plus modified FOLFOX 6 in patients with metastatic pancreatic cancer	NCT01666730 (Link)  https://clinicaltrials.gov/ct2/show/NCT01666730?term=NCT01666730&rank=1	Active, not recruiting	50 18 years and older (adult, older adult) All sex	August 14, 2012 to March 2019 (estimated study completion date)	Drug: metformin (given orally) oxaliplatin, leucovorin calcium, and fluorouracil (given IV) Other: laboratory biomarker analysis correlative studies	1. Acinar cell adenocarcinoma of the pancreas 2. Duct cell adenocarcinoma of the pancreas 3. Recurrent pancreatic cancer 4. Stage IV pancreatic cancer	Metformin improved patients’ PFS and OS
An exploratory study of metformin with or without rapamycin as maintenance therapy after induction chemotherapy in subjects with metastatic pancreatic adenocarcinoma	NCT02048384 (Link)  https://clinicaltrials.gov/ct2/show/NCT02048384?term=NCT02048384&rank=1	Active, not recruiting	22 18 years and older (adult, older adult) All Sex	January 23, 2014 to December 2020	Drug: metformin alone Drug: rapamycin + metformin	Metastatic pancreatic adenocarcinoma	Metformin inhibits mTOR activity peripheral blood mononuclear cells (PBMC) of subjects treated with metformin with or without rapamycin
Phase II study of metformin in a pre-prostatectomy prostate cancer cohort	NCT01433913 (Link)  https://clinicaltrials.gov/ct2/show/NCT01433913?term=NCT01433913&rank=1	Completed	20 18 years and older (adult, older adult) Male	September 9, 2011 to April 2014	Drug: metformin and placebo (given orally) Other: laboratory biomarker analysis correlative studies	1. Adenocarcinoma of the prostate 2. Recurrent prostate cancer 3. Stage I prostate cancer 4. Stage IIA prostate cancer 5. Stage IIB prostate cancer	Metformin has effects on apoptosis, cell cycle regulation, mTOR regulation, angiogenesis and AMPK activation that lead prevents cancer cells growth
Effect of the addition of metformin hydrochloride on the prognosis of patients with B-cell precursor (Ph+ negative) acute lymphoblastic leukemia with high expression of ABCB1 gene	NCT03118128 (Link)  https://clinicaltrials.gov/ct2/show/NCT03118128?term=NCT03118128&rank=1	Completed	102 18 years to 70 years (adult, older adult) All sex	January 1, 2015 to December 1, 2016	Drug: metformin (metformin 850 mg PO three times a day plus prednisone in one 7-day cycle as pre-treatment and during the 28 days induction remission treatment, consolidation therapy and maintenance)	Acute lymphoblastic leukemia	Beneficial effects of metformin on relapse rate and patients’ RFS
APphase I study of temsirolimus in combination with metformin in advanced solid tumors	NCT00659568 (Link)  https://clinicaltrials.gov/ct2/show/NCT00659568?term=NCT00659568&rank=1	Completed	28 18 years and older (adult, older adult) All sex	April 15, 2008 to February 2010	Drug: metformin hydrochloride Drug: temsirolimus	1. Breast cancer 2. Endometrial cancer 3. Kidney cancer 4. Lung cancer 5. Lymphoma 6. Unspecified adult solid tumor, protocol specific	Metformin improved patients’ survival and has antitumor activity, including tumor response rate and time to progression
Phase II study of metformin and 5-fluorouracil in patients with advanced colorectal cancer previously treated with oxaliplatin and irinotecan based chemotherapy	NCT01941953 (Link)  https://clinicaltrials.gov/ct2/show/NCT01941953?term=NCT01941953&rank=1	Completed	50 16 years and older (child, adult, older adult) All sex	September 4, 2013 to November 2014	Drug: metformin and fluorouracil (metformin 850 mg PO BID plus 5FU 425 mg/m2+ leucovorin 50 mg IV weekly)	Metastatic colorectal cancer	Metformin improved patients’ OS and PFS
A pilot study of metformin as a chemoprevention agent in non-small cell lung cancer	NCT01717482 (Link)  https://clinicaltrials.gov/ct2/show/NCT01717482?term=NCT01717482&rank=1	Active, not recruiting	24 18 years and older (adult, older adult) All sex	October 25, 2012 to June 2019	Drug: metformin Other: placebo comparator (standard of care observation)	1. Lung neoplasms 2. Carcinoma, non-small-cell lung	Metformin decreased level of Ki67

Figure 2 Overview of the indirect (A) and direct (B) molecular mechanism of metformin.

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