Table 1.

Epidemiologic studies of metformin and cancer risk

First author (ref.) (country)Study designEndpointSample sizeRisk estimates (95% CI)Treatment comparisonAdjusting variables (other than age and sex)
UKPD Study Group (49) (UK)RCTMortalityCases: 139 At risk: 753Any site: 0.71 (0.29–1.76)aDiet alone (n = 411) vs. intensive blood-glucose control policy with metformin (n = 342)n.a.
Schernthaner (61,72) QUARTET M (Europe)RCTIncidenceCases: 9At risk: 1,194Any site: 0.51 (0.14–1.90)Metformin monotherapy (n = 597) vs. pioglitazone (n = 597)n.a.
Hanefeld (62,72) QUARTET C (Europe and North America)RCTIncidenceCases: 9At risk: 639Any site: 1.99 (0.43–12.32)Metformin + sulfonylurea (n = 320) vs. pioglitazone + sulfonylurea (n = 319)n.a.
Yang (85) (UK)General practice nested case–control in a retrospective cohortIncidenceCases: 125 Controls: 1,195Colon: 1.00 (0.60–1.70)3 or more years of metformin therapy vs. noninsulin usersSmoking, history of cholecystectomy, diabetes duration, BMI, sulfonylurea use, aspirin/NSAID use
Bowker (69) (Canada)Population-based retrospective cohortMortalityCases: 407At risk: 10,309Any site: 0.77 (0.63–0.91)Metformin vs. sulfonylureas useInsulin use and CDS.
Monami (55) (Italy)Hospital-based retrospective case–control studyIncidenceCases: 195 Controls: 195Any site: 0.28 (0.13–0.57)Exposure to metformin for more than 36 months vs. other hypoglycemic drugs usersDuration of diabetes, BMI, HbA1c, comorbidity, smoking and alcohol abuse, concomitant hypoglycemic treatment
Oliveria (76) (USA)Population-based retrospective cohortIncidenceCases: 813At risk: 191,223Colon: 0.67 (0.52–0.85) Bladder: 0.99 (0.70–1.39) Liver: 0.73 (0.34–1.56) Pancreas: 1.26 (0.80–1.99)Ever use of metformin monotherapy vs. never useHBV and HCV infection, cirrhosis, alcoholism, polyps, obesity, ulcerative colitis, Crohn's disease, cystic fibrosis, chronic pancreatitis, dermatomyositis, polymyositis, idiopathic DVT, partial gastrectomy, pelvic radiation, and schistosomiasis.
Currie (59) (UK)General practice retrospective cohortIncidenceCases: 373At risk: 7,897Any site: 0.74 (0.65–0.84); Breast: 1.02 (0.71–1.45); Colon: 0.56 (0.40–0.76); Prostate: 0.93 (0.67–1.32); Pancreas: 0.20 (0.11–0.36)Metformin monotherapy vs. sulfonylureas monotherapySmoking, comorbidity, HbA1c, diabetes duration, weight
Donadon (80) (Italy)Hospital-based retrospective case–controlIncidenceCases: 465 Controls: 490Liver: 0.33 (0.10–0.70)Metformin users vs. nonusersNo adjusting variables were considered
Home (52) RECORD, (Europe)RCTIncidenceCases: 125At risk: 2,225Any site: 1.22 (0.86–1.74) Breast: 1.0 (0.32–3.10)b Prostate: 2.0 (0.68–5.82)b Pancreas: 5.99 (0.72–49.6)b Liver: 4.0 (0.18–88.7)bMetformin (n = 1,122) vs. rosiglitazone (n = 1,103)n.a.
Li (86) (USA)Hospital-based retrospective case–controlIncidenceCases: 255 Controls: 106Pancreas: 0.38 (0.22–0.69)Metformin users vs. nonusersRace, smoking, alcohol, BMI, family history of cancer, duration of diabetes, and insulin use.
Libby (54) (Scotland, UK)Population-based retrospective cohortIncidence and mortalityCases: 771At risk: 8,170Any site incidence: 0.63 (0.53–0.75); Breast: 0.60 (0.32–1.10); Colon: 0.60 (0.38–0.94); Lung: 0.70 (0.43–1.15) Any site mortality: 0.63 (0.49–0.81)Metformin users vs. nonusersSmoking, BMI, HbA1c, material deprivation, other drug use (sulfonylureas or insulin)
Wright (79) (USA)Population-based retrospective case–controlIncidenceCases: 97 Controls: 101Prostate: 0.56 (0.32–1.00)Metformin users vs. nonusersBMI, statin and aspirin use, other diabetes treatment, PSA screening history, family history of prostate cancer
Bodmer (73) (UK)General practice retrospective nested case–controlIncidenceCases: 17 Controls: 120Breast: 0.44 (0.24–0.82)Users of 40+ prescriptions (>5 years) of metformin vs. nonuserscGeneral practice and calendar time by matching, other use of prandial glucose regulators, acarbose, estrogens, smoking, BMI, diabetes duration, and HbA1c
Hassan (81) (USA)Hospital-based retrospective case–controlIncidenceCases: 122 Controls: 86Liver: 0.30 (0.20–0.60)Biguanide users vs. nonusersRace, educational level, cigarette smoking, alcohol drinking, HCV, HBV, family history of cancer
Kahn (63) ADOPT (USA)RCTIncidenceCases: 160At risk: 4,351Any site: ADOPT-G: 0.78 (0.53–1.14)ADOPT-R: 0.92 (0.63–1.35)Breast: 2.0 (0.60–6.62)b Colon: 1.75 (0.51–5.96)b Prostate: 1.0 (0.41–2.40)b Pancreas: 0.1 (0.005–1.84)bMetformin (n = 1,454) vs. glibencamide (n = 1,441) vs. rosiglitazone (n = 1,456)n.a.
Landman (70) (Netherlands)General practice prospective cohortMortalityCases: 122At risk: 1,353Any site: 0.43 (0.23–0.80)Metformin users vs. nonusersSmoking, diabetes duration, HbA1c, serum creatinine, BMI, blood pressure, total cholesterol/HDL, albuminuria, insulin use, sulfonylurea use and macrovascular complications
Williams-Herman (64) (18 countries worldwide)RCTIncidenceCases: 18At risk: 543Any site: 0.61 (0.22–1.79)Metformin (n = 364) vs. Sitagliptin (n = 179)n.a.
Yang (58) (China)Hospital-based prospective cohortIncidenceCases: 271At risk: 6,103Any site: 0.99 (0.70, 1.41)Sulfonylurea use + ever use of metformin vs. never use of metforminBMI, smoking status, alcohol, HbA1c, SBP, LDL-C–related risk, HDL and triglyceride, statins, RAS inhibitor usage, insulin usage
Azoulay (77) (Canada)Population-based retrospective nested case–controlIncidenceCases: 739 Controls: 7,359Prostate: 1.23 (0.99–1.52)Ever vs. never users of metformincHbA1c, alcohol use, obesity, smoking, lower urinary tract symptoms, previous cancer, previous use of NSAID, antihypertensive drugs, and statins, use of other antidiabetic agents
Baur (65) (Germany)Hospital-based prospective cohortIncidence and mortalityCases: 66At risk: 1,308Any site incidence: 0.66 (0.26–1.64)Any site mortality: 0.71 (0.2–2.59)Metformin users vs. nonusersSmoking, BMI, HbA1c
Bosco (74) (Denmark)Population-based retrospective nested case–controlIncidenceCases: 393 Controls: 3,930Breast: 0.81 (0.63–0.96)Metformin for at least 1 year vs. women not prescribed antidiabetic medication, or used metformin for at least 1 yearDiabetes complications, clinical obesity year of birth, parity, postmenopausal hormone use.
Ferrara (75) (USA)Population-based prospective cohortIncidenceCases: 9,082At risk: 252,467Breast: 0.90 (0.80–1.00); Colon: 1.00 (0.90–1.20); Prostate: 1.00 (0.90–1.10); Pancreas: 1.20 (1.00–1.50); Lung: 1.00 (0.80–1.10); NHL: 1.00 (0.80–1.20); Corpus Uteri: 0.90 (0.80–1.20); Kidney/renal pelvis: 1.30 (1.0–1.6); Rectum: 0.90 (0.70–1.20); Melanoma: 0.80 (0.60–1.10)Ever use of pioglitazone and metformin vs. never use of metforminYear of cohort entry, race/ethnicity, income, smoking, glycemic control, diabetes duration, creatinine levels, congestive heart failure, use of other diabetes medications
Hense (51) (Germany)Population-based prospective cohortIncidenceCases: 1,364At risk: 26,742Any site: 0.95 (0.90–1.01)Metformin (only) users vs. nonusersDiabetes duration, BMI, insulin therapy
Lai (84) (Taiwan)Population-based retrospective cohortIncidenceCases: 129At risk: 19,624Lung: 0.55 (0.37–0.82)Metformin users vs. nonusersPulmonary tuberculosis, chronic obstructive pulmonary disease, and propensity score (quintile).
Lee (53) (South Korea)Population-based prospective cohortIncidenceCases: 339At risk: 15,717Any site: 0.12 (0.08–0.19); Colon: 0.36 (0.13–0.98); Liver: 0.06 (0.02–0.16); Esophagus: 0.44 (0.07–2.61); Stomach: 1.41 (0.42–4.73)At least 2 prescription of metformin vs. any other oral antihyperglycemic medicationOther oral antihyperglycemic medication, Charlson comorbidity index score, metformin dosage and duration
Mellbin (71) (Sweden)Prospective cohort follow-up analysis from RCTMortalityN = 1,073N events = 37Any site: 0.25 (0.08–0.83)Patients using metformin vs. not using at dischargeSmoking habits, previous myocardial infarction or previous congestive heart failure, creatinine at randomization, percutaneous transluminal coronary angioplasty or coronary artery bypass grafting during the hospitalization, and mean updated blood glucose
Morden (56) (USA)General practice retrospective cohortIncidenceCases: 5,466At risk: 81,681Any site: 1.01 (0.94–1.08); Breast: 1.28 (1.05–1.57); Colon: 0.94 (0.72–1.22); Prostate: 0.97 (0.76–1.24); Pancreas: 1.25 (0.89–1.75)Metformin vs. not in insulin-treated patientsRace, low-income subsidy status, comorbidities, tobacco exposure, Charlson, comorbidities excluding malignancy, diabetes, insulin dose quartiles
Bo (68) (Italy)Hospital-based retrospective cohortMortalityCases: 122At risk: 3,703Any site: 0.56 (0.34–0.94)Metformin use vs. diet control onlyDiabetes duration, HbA1c, smoking, BMI, presence of retinopathy, nephropathy, coronary or peripheral artery disease, other co-morbidities and the use of antihypertensive drugs and acetylsalicylic acid
Bodmer (83) (UK)General practice retrospective nested case–controlIncidenceCases: 920 Controls: 5,519Colon: 1.43 (1.08–1.90)Metformin users (50+ prescriptions) vs. nonusersDiabetes duration, BMI, smoking, prior use of aspirin, NSAID, statins, estrogen use (women), sulfonylureas and insulin use
Bodmer (82) (UK)General practice retrospective case–controlIncidenceCases: 307 Controls: 1,347Pancreas: 0.83 (0.57–1.21)Metformin users vs. nonusersBMI, smoking, alcohol consumption, diabetes duration, other antidiabetics drugs
Bodmer (88) (UK)General practice retrospective case–controlIncidenceCases: 1.029 Controls: 6,174Lung: 1.09 (0.85–1.38)Metformin users (40+ prescriptions) vs. nonusersBMI and smoking
Chlebowski (48,95) (USA)Prospective Cohort (WHI program)IncidenceCases: 233At risk: 68,019Breast: 0.65 (0.46–0.91)Metformin vs. other antidiabetic drugsFamily history, prior breast biopsy, age at menarche, menopause, parity, age at first live birth, breastfeeding, education, smoking, alcohol use, BMI, physical activity, duration of prior estrogen alone, estrogen + progesterone use, bilateral oophorectomy, weight loss
Hsieh (89) (Taiwan)Population-based prospective cohortIncidenceCases: 6.554At risk: 61,777Any site: 0.56 (0.44–0.71) Breast: 0.57(0.33–0.97) Colon: 0.54 (0.39–0.76) Prostate: 0.97 (0.60–1.55) Lung: 0.64 (0.45–0.90)Liver: 0.66 (0.49–0.91) Pancreas: 0.63 (0.28–1.42) Stomach: 0.63 (0.39–1.08)Metformin vs. sulfonylureaOnly age and sex
Lehman (78) (USA)Population-based retrospective cohortIncidenceCases: 360At risk: 5,042Prostate: 2.15 (1.83–2.52)Metformin versus sulfonylurea only (restricted to nonstatin users)cHbA1c, diabetes duration, race/ethnicity, Charlson comorbidity score
Liao (91) (Taiwan)Population-based prospective cohortIncidenceCases: 56At risk: 49,803Pancreas: 0.85 (0.39–1.89)Metformin users vs. nonusersNo adjusting variables were considered
Magliano (66) (Australia)Community-based longitudinal cohortIncidenceCases: 309At risk: 1,294Any site: 0.88 (0.67–1.17); Prostate: 2.16 (1.19–3.9)Metformin users vs. nonusersNo adjusting variables were considered
Mazzone (94) (USA)Hospital-based retrospective case–controlIncidenceCases: 507 Controls: 507Lung: 0.48 (0.28–0.81)Metformin users vs. nonusersMedication use, BMI, HbA1C, smoking
Ngwana (50) (Belgium)General practice retrospective cohortIncidenceCases: 221At risk: 4,012Any site: 0.20 (0.03–1.64); Breast: 0.46 (0.07–3.10); Colon: 0.11 (0.01–1.07); Prostate: 0.61 (0.31–1.19)Metformin vs. other antidiabetic treatments and diet onlyWeight and initial HbA1c
Redaniel (90) (UK)General practice retrospective cohortIncidenceCases: 873At risk: 52,657Breast: 1.02 (0.79–1.3)Metformin vs. sulfonylureaPeriod, region, BMI, year of diagnosis
Ruiter (57) (Netherlands)Hospital-based prospective cohortIncidenceCases: 3,552At risk: 85,289Any site: 0.90 (0.88–0.91); Breast: 0.95 (0.91–0.98); Colon: 0.91 (0.88–0.94); Prostate: 0.92 (0.88–0.94); Pancreas: 0.73 (0.66–0.80); Liver: 0.67 (0.53–0.86); Lung: 0.87 (0.84–0.91); Esophagus: 0.90 (0.82–0.97); Stomach: 0.83 (0.76–0.90)Metformin vs. sulfonylurea derivativescAge at first oral glucose-lowering drug prescription, number of other drugs used in the year before the start of OGLD, number of hospitalizations in the year before the start of OGLD, calendar time
Becker (96) (UK)General practice retrospective case–controlIncidenceCases: 291 Controls: 1,746Endometrial: 0.88 (0.58–1.32)Metformin users (25+ prescriptions) vs. no prior useBMI, smoking, diabetes duration
Chaiteerakij et al. (93) (USA)Hospital-based retrospective case–controlIncidenceCases: 105 Controls: 34Liver: 0.4 (0.2–0.9)Metformin users vs. nonusersEthnicity, and residential area, propensity scores for statin-use
Chen (92) (Taiwan)Population-based retrospective case–controlIncidenceCases: 22,047 Controls: 25,773Liver: 0.79 (0.75–0.83)Metformin users vs. nonusersCirrhosis, HCV, DM duration, comorbidities, other medications
Chung (67) (South Korea)Population-based retrospective cohortIncidenceCases: 73At risk: 1,217Any site: 0.57 (0.39–0.85)Metformin users vs. nonusersNot specified
Currie (60) (UK)General practice retrospective cohortIncidenceCases: 4,029At risk: 84,622Any site: 0.91 (0.83–1.00)Metformin vs. sulfonylureaSystolic blood pressure, HbA1c, total cholesterol, serum creatinine, BMI, smoking status, antihypertensive lipid-lowering, antiplatelet therapy, duration of diabetes, prior history of cancer, LVD, microvascular disease, number of contacts with the general practitioner in the year before the index date, Charlson comorbidity index
Smiechowski (87) (Canada)Population-based prospective nested case–controlIncidenceCases: 808 Controls:7,764Lung: 0.94 (0.76–1.17)Metformin users vs. nonusersDiabetes duration, HbA1c, obesity, smoking, excessive alcohol use, previous cancer, chronic obstructive pulmonary disease, asthma, nonsteroidal anti-inflammatory drugs, aspirin, statins, and other antidiabetic drugs

Abbreviations: ADOPT, a diabetes outcome progression trial; %CI, percent CI; CDS, chronic disease score; DVT, deep vein thrombosis; HbA1c, hemoglobin A1c; HBV, hepatitis B virus; HCV, hepatitis C virus; HDL, high-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; N, number; NSAID, nonsteroidal anti-inflammatory drug; OGLD, oral glucose lowering drugs; PSA, prostate-specific antigen; RAS, renin–angiotensin system; RCT, randomized controlled trial; RECORD, rosiglitazone evaluated for cardiac outcomes and regulation of glycaemia in diabetes; SBP, systolic blood pressure; UKPDS, United Kingdom Prospective Diabetes Study.

  • aRisk estimate for users of metformin alone.

  • bADOPT-G and ADOPT-R, glibenclamide and rosiglitazone arms of ADOPT study. Risk estimates represent multiple comparisons from a single trial, and the analysis takes account of correlation between these comparisons; risk estimates for single cancer sites were calculated from crude data.

  • cExcluded patients on monotherapy with insulin.