Table 1.
Epidemiological studies of metformin and cancer risk.
| First Author, ref year (Country) | Study design | Endpoint | Sample size | Risk Estimates (95%CI) | Treatment comparison | Adjusting variables(other than age & sex) |
|---|---|---|---|---|---|---|
| UKPD Study Group 49, 1998 (UK) | RCT | mortality | Cases: 139 At risk: 753 |
Any site: 0.71 (0.29–1.76) † | diet alone (n=411) vs. intensive blood-glucose control policy with metformin (n=342). | n.a. |
| Schernthaner G 61,72 2004 QUARTET M (Europe) | RCT | incidence | Cases: 9 At risk: 1.194 |
Any site: 0.51 (0.14–1.90) | metformin monotherapy (n=597) vs. pioglitazone (n=597) | n.a. |
| Hanefeld M, 62,72 2004 QUARTET C (Europe and North America) | RCT | incidence | Cases: 9 At risk: 639 |
Any site: 1.99 (0.43–12.32) | metformin+sulfonylurea (n=320) vs. pioglitazone+ sulfonylurea (n=319) | n.a. |
| Yang YX 85, 2004 (UK) | General practice nested case-control in a retrospective cohort | incidence | Cases: 125 Controls: 1.195 |
Colon: 1.00 (0.60–1.70) | 3 or more years of metformin therapy vs. non-insulin users | Smoking, history of cholecystectomy, diabetes duration, BMI, sulphonylurea use, aspirin/NSAID use |
| Bowker SL 69, 2006 (Canada) | Population-based retrospective cohort | mortality | Cases: 407 At risk: 10.309 |
Any site: 0.77 (0.63–0.91) | metformin vs. sulfonylureas use | insulin use and CDS. |
| Monami M 55, 2009 (Italy) | Hospital-based retrospective case-control study | incidence | Cases: 195 Controls: 195 |
Any site: 0.28 (0.13–0.57) | exposure to metformin for more than 36 months vs. other hypoglycemic drugs users | duration of diabetes, BMI, HbA1c, comorbidity, smoking and alcohol abuse, concomitant hypoglycemic treatment |
| Oliveria SA 76, 2008 (USA) | Population-based retrospective cohort | incidence | Cases: 813 At risk: 191.223 |
Colon 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 use | HBV 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 CJ 59, 2009 (UK) | General practice retrospective cohort | incidence | Cases: 373 At risk: 7.897 |
Any 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 monotherapy | Smoking, comorbidity, HbA1c, diabetes duration, weight |
| Donadon V 80, 2009 (Italy) | Hospital-based retrospective case-control | incidence | Cases: 465 Controls: 490 |
Liver: 0.33 (0.10–0.70) | metformin users vs. nonusers | No adjusting variables were considered |
| Home PD 52, 2009, RECORD, (Europe) | RCT | incidence | Cases: 125 At risk: 2.225 |
Any site: 1.22 (0.86–1.74) Breast: 1.0 (0.32–3.10)* Prostate: 2.0 (0.68–5.82)* Pancreas: 5.99 (0.72–49.6)* Liver: 4.0 (0.18–88.7)* |
metformin (n=1122) vs. rosiglitazone (n=1103) | n.a. |
| Li D 86, 2009 (USA) | Hospital-based retrospective case-control | incidence | Cases: 255 Controls: 106 |
Pancreas: 0.38 (0.22–0.69) | metformin users vs. nonusers | race, smoking, alcohol, BMI, family history of cancer, duration of diabetes, and insulin use. |
| Libby G 54, 2009 (Scotland, UK) | Population-based retrospective cohort | incidence & mortality | Cases: 771 At risk: 8.170 |
Any 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. nonusers | Smoking, BMI, HbA1c, material deprivation, other drug use (sulphonylureas or insulin) |
| Wright JL 79, 2009 (USA) | Population-based retrospective case-control | incidence | Cases: 97 Controls: 101 |
Prostate: 0.56 (0.32–1.00) | metformin users vs. nonusers | BMI, statin and aspirin use, other diabetes treatment, PSA screening history, family history of PCa |
| Bodmer M 73, 2010 (UK) | General practice retrospective nested case-control | incidence | Cases: 17 Controls: 120 |
Breast: 0.44 (0.24–0.82) | users of 40+ prescriptions (>5 years) of metformin vs. nonusers# | General practice and calendar time by matching, other use of prandial glucose regulators, acarbose, estrogens, smoking, BMI, diabetes duration and HbA1c |
| Hassan MM 81, 2010 (USA) | Hospital-based retrospective case-control | incidence | Cases: 122 Controls: 86 |
Liver: 0.30 (0.20–0.60) | biguanide users vs. nonusers | Race, educational level, cigarette smoking, alcohol drinking, HCV, HBV, family history of cancer |
| Kahn SE 63, 2006 ADOPT, (USA) | RCT | incidence | Cases: 160 At risk: 4.351 |
Any site: ADOPT-G: 0.78 (0.53–1.14) ADOPT-R: 0.92 (0.63–1.35) Breast: 2.0 (0.60–6.62)* Colon: 1.75 (0.51–5.96)* Prostate: 1.0 (0.41–2.40)* Pancreas: 0.1 (0.005–1.84)* |
metformin (n=1454) vs. glibencamide (n=1441) vs. rosiglitazone (n=1456) | n.a. |
| Landman GWD 70, 2010 (Netherlands) | General practice prospective cohort | mortality | Cases: 122 At risk: 1.353 |
Any site: 0.43 (0.23–0.80) | metformin users vs. nonusers | Smoking, diabetes duration, HbA1c, serum creatinine, BMI, blood pressure, total cholesterol/HDL, albuminuria, insulin use, sulphonylurea use and macrovascular complications |
| Williams-Herman D,2010 64 (18 countries worldwide) | RCT | incidence | Cases: 18 At risk: 543 |
Any site: 0.61 (0.22–1.79) | Metformin (n=364) vs. Sitagliptin (n=179) | n.a. |
| Yang X 58, 2010 (China) | Hospital-based prospective cohort | incidence | Cases: 271 At risk: 6.103 |
Any site: 0.99 (0.70, 1.41) | sulphonylurea use + ever use of metformin vs. never use of metformin | BMI, smoking status, alcohol, HbA1c, SBP, LDL-C related risk, HDL and triglyceride, statins, RAS inhibitor usage, insulin usage. |
| Azoulay L 77, 2011 (Canada) | Population-based retrospective nested case-control | incidence | Cases: 739 Controls: 7.359 |
Prostate: 1.23 (0.99–1.52) | ever vs. never users of metformin# | HbA1c, alcohol use, obesity, smoking, lower urinary tract symptoms, previous cancer, previous use of NSAID, antihypertensive drugs, and statins, use of other antidiabetic agents |
| Baur DM 65, 2011 (Germany) | Hospital-based prospective cohort | incidence & mortality | Cases: 66 At risk: 1.308 |
Any site incidence: 0.66 (0.26–1.64) Any site mortality: 0.71 (0.2–2.59) |
metformin users vs. nonusers | Smoking, BMI, HbA1c |
| Bosco JLF 74, 2011 (Denmark) | Population-based retrospective nested case-control | incidence | Cases: 393 Controls: 3.930 |
Breast: 0.81 (0.63–0.96) | metformin for at least 1 yr vs. women not prescribed antidiabetic medication, or used metformin for at least 1 yr. | diabetes complications, clinical obesity year of birth, parity, postmenopausal hormone use. |
| Ferrara A 75, 2011 (USA) | Population-based prospective cohort | incidence | Cases: 9.082 At risk: 252.467 |
Breast: 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 metformin | year of cohort entry, race/ethnicity, income, smoking, glycemic control, diabetes duration, creatinine levels, congestive heart failure, use of other diabetes medications |
| Hense HW 51, 2011 (Germany) | Population-based prospective cohort | incidence | Cases: 1.364 At risk: 26.742 |
Any site: 0.95 (0.90–1.01) | metformin (only) users vs. nonusers | diabetes duration, BMI, insulin therapy |
| Lai SW 84, 2011 (Taiwan) | Population-based retrospective cohort | incidence | Cases: 129 At risk: 19.624 |
Lung: 0.55 (0.37–0.82) | metformin users vs. nonusers | pulmonary tuberculosis, chronic obstructive pulmonary disease, and propensity score (quintile). |
| Lee JH 53, 2011 (South Korea) | Population-based prospective cohort | incidence | Cases: 339 At risk: 15.717 |
Any 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 medication | other oral antihyperglycemic medication, Charlson comorbidity index score, metformin dosage and duration |
| Mellbin LG 71, 2011 (Sweden) | Prospective cohort follow-up analysis from RCT | mortality | N=1073 N events=37 |
Any site: 0.25 (0.08–0.83) | patients using metformin vs. not using at discharge | smoking habits, previous myocardial infarction or previous congestive heart failure, creatinine at randomisation, percutaneous transluminal coronary angioplasty or coronary artery bypass grafting during the hospitalisation, and mean updated blood glucose |
| Morden NE 56, 2011 (USA) | General-practice retrospective cohort | incidence | Cases: 5.466 At risk: 81.681 |
Any 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 patients | race, low-income subsidy status, comorbidities, tobacco exposure, Charlson, comorbidities excluding malignancy, diabetes, insulin dose quartiles |
| Bo S 68, 2012 (Italy) | Hospital-based retrospective cohort | mortality | Cases: 122 At risk: 3.703 |
Any site: 0.56 (0.34–0.94) | metformin use vs. diet control only | diabetes 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 M 83, 2012 (UK) | General-practice retrospective nested case-control | incidence | Cases: 920 Controls: 5.519 |
Colon: 1.43 (1.08–1.90) | metformin users (50+ prescriptions) vs. non users | Diabetes duration, BMI, smoking, prior use of aspirin, NSAID, statins, estrogen use (women), sulphonylureas and insulin use |
| Bodmer M 82, 2012 (UK) | General-practice retrospective case-control | incidence | Cases: 307 Controls: 1.347 |
Pancreas: 0.83 (0.57–1.21) | metformin users vs. nonusers | BMI, smoking, alcohol consumption, diabetes duration, other antidiabetics drugs |
| Bodmer M 88, 2012 (UK) | General-practice retrospective case-control | incidence | Cases: 1.029 Controls: 6.174 |
Lung: 1.09 (0.85–1.38) | metformin users (40+ prescriptions) vs. non users | BMI and smoking |
| Chlebowski RT 48,95, 2013 (USA) | Prospective Cohort (WHI program) | incidence | Cases: 233 At risk: 68.019 |
Breast: 0.65 (0.46–0.91) | metformin vs. other antidiabetic drugs | Family 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 MC 89, 2012 (Taiwan) | Population-based prospective cohort | incidence | Cases: 6.554 At risk: 61.777 |
Any 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. sulfonylurea | Only age and sex |
| Lehman DM 78, 2012 (USA) | Population-based Retrospective Cohort | incidence | Cases: 360 At risk: 5.042 |
Prostate: 2.15 (1.83–2.52) | metformin versus sulfonylurea only (restricted to non-statin users)# | HbA1c, diabetes duration, race/ethnicity, Charlson comorbidity score. |
| Liao KF 91, 2012 (Taiwan) | Population-based prospective cohort | incidence | Cases: 56 At risk: 49.803 |
Pancreas: 0.85 (0.39–1.89) | metformin users vs. nonusers | No adjusting variables were considered |
| Magliano DJ 66, 2012 (Australia) | Community-based longitudinal cohort | incidence | Cases: 309 At risk: 1.294 |
Any site: 0.88 (0.67–1.17); Prostate: 2.16 (1.19–3.9) |
metformin users vs. nonusers | No adjusting variables were considered |
| Mazzone PJ 94, 2012, (USA) | Hospital-based retrospective case-control | incidence | Cases: 507 Controls: 507 |
Lung: 0.48 (0.28–0.81) | metformin users vs. nonusers | medication use, BMI, HbA1C, smoking |
| Ngwana G 50, 2012 (Belgium) | General-practice retrospective cohort | incidence | Cases: 221 At risk: 4012 |
Any 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 only | weight and initial HbA1c |
| Redaniel MT 90, 2012 (UK) | General practice retrospective cohort | incidence | Cases: 873 At risk: 52657 |
Breast: 1.02 (0.79–1.3) | metformin vs. sulfonylurea | period, region, BMI, year of diagnosis. |
| Ruiter R 57, 2012 (Netherlands) | Hospital-based prospective cohort | incidence | Cases: 3.552 At risk: 85.289 |
Any 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. sulphonylurea derivatives# | Age 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 C 96, 2013 (UK) | General practice retrospective case-control | incidence | Cases: 291 Controls: 1.746 |
Endometrial: 0.88 (0.58–1.32) | metformin users (25+ prescriptions) vs. no prior use | BMI, smoking, diabetes duration |
| Chaiteerakij R 93, 2013 (USA) | Hospital-based retrospective case-control | incidence | Cases: 105 Controls: 34 |
Liver: 0.4 (0.2–0.9) | metformin users vs. nonusers | ethnicity, and residential area, propensity scores for statin-use |
| Chen HP 92, 2013 (Taiwan) | Population-based Retrospective case-control | incidence | Cases: 22.047 Controls: 25.773 |
Liver: 0.79 (0.75–0.83) | metformin users vs. nonusers | Cirrhosis, HCV, DM duration, Comorbidities, other medications |
| Chung HE 67, 2013 (South Korea) | Population-based retrospective cohort | incidence | Cases: 73 At risk: 1.217 |
Any site: 0.57 (0.39–0.85) | metformin users vs. nonusers | Not specified |
| Currie CJ 60, 2013 (UK) | General practice retrospective cohort | incidence | Cases: 4.029 at risk: 84.622 |
Any site: 0.91 (0.83–1.00) | metformin vs. sulfonylurea | systolic 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 prior to the index date, Charlson comorbidity index |
| Smiechowski et al. 87, 2013 (Canada) | Population-based prospective nested case-control | incidence | Cases: 808 Controls: 7764 |
Lung: 0.94 (0.76–1.17) | metformin users vs. nonusers | diabetes duration, HbA1c, obesity, smoking, excessive alcohol use, previous cancer, chronic obstructive pulmonary disease, asthma, nonsteroidal anti-inflammatory drugs, aspirin, statins, and other antidiabetic drugs |
%CI- Percent Confidence Interval, UKPDS- United Kingdom Prospective Diabetes Study, RCT- Randomized Controlled Trial, N- number, BMI- Body Mass Index, NSAID- Non-steroidal Anti-inflammatory drug, CDS- chronic disease score, HbA1c - haemoglobin A1c, HBV- Hepatitis B Virus, HCV- Hepatitis C Virus, DVT- Deep Vein Thrombosis, HDL- High Density Lipoprotein, PSA- Prostate specific antigen, PCa- Prostate Cancer, ADOPT- A Diabetes Outcome Progression Trial, RECORD- Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes, SBP- systolic blood pressure, LDL-C- low density lipoprotein cholesterol, RAS- renin–angiotensin system, OGLD- oral glucose lowering drugs;
†
risk estimate for users of metformin alone;
*
ADOPT-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;
#
Excluded patients on monotherapy with insulin.