New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes

Gillian Libby, Louise A Donnelly, Peter T Donnan, Dario R Alessi, Andrew D Morris, Josie M M Evans, Gillian Libby, Louise A Donnelly, Peter T Donnan, Dario R Alessi, Andrew D Morris, Josie M M Evans

Abstract

Objective: The antidiabetic properties of metformin are mediated through its ability to activate the AMP-activated protein kinase (AMPK). Activation of AMPK can suppress tumor formation and inhibit cell growth in addition to lowering blood glucose levels. We tested the hypothesis that metformin reduces the risk of cancer in people with type 2 diabetes.

Research design and methods: In an observational cohort study using record-linkage databases and based in Tayside, Scotland, U.K., we identified people with type 2 diabetes who were new users of metformin in 1994-2003. We also identified a set of diabetic comparators, individually matched to the metformin users by year of diabetes diagnosis, who had never used metformin. In a survival analysis we calculated hazard ratios for diagnosis of cancer, adjusted for baseline characteristics of the two groups using Cox regression.

Results: Cancer was diagnosed among 7.3% of 4,085 metformin users compared with 11.6% of 4,085 comparators, with median times to cancer of 3.5 and 2.6 years, respectively (P < 0.001). The unadjusted hazard ratio (95% CI) for cancer was 0.46 (0.40-0.53). After adjusting for sex, age, BMI, A1C, deprivation, smoking, and other drug use, there was still a significantly reduced risk of cancer associated with metformin: 0.63 (0.53-0.75).

Conclusions: These results suggest that metformin use may be associated with a reduced risk of cancer. A randomized trial is needed to assess whether metformin is protective in a population at high risk for cancer.

Figures

Figure 1
Figure 1
Flowchart showing how metformin users and comparators were selected for the study.
Figure 2
Figure 2
Kaplan-Meier plot with 95% CIs showing time to cancer among metformin users and comparators.

References

    1. Hardie DG: AMP-activated protein kinase as a drug target. Annu Rev Pharmacol Toxicol 2007; 47: 185– 210
    1. Schneider MB, Matsuzaki H, Haorah J, Ulrich A, Stabdop J, Ding XZ, Adrian TE, Pour PM: Prevention of pancreatic induction in hamsters by metformin. Gastroenterology 2001; 120: 1263– 1270
    1. Anisimov VN, Egormin PA, Bershtein LM, Zabezhinskii MA, Piskunova TS, Popovich IG, Semenchenko IV: Metformin decelerates aging and development of mammary tumors in HER-2/neu transgenic mice. Bull Exp Biol Med 2005; 139: 721– 723
    1. Huang X, Wellschleger S, Shapiro N, McGuire VA, Sakamoto K, Woods YL, McBurnie W, Fleming S, Alessi DR: Important role of the LKB1-AMPK pathway in suppressing tumorigenesis in PTEN-deficient mice. Biochem J 2008; 412: 211– 221
    1. Zakikhani M, Dowling R, Fantus IG, Sonenberg N, Pollak M: Metformin is an AMP kinase–dependent growth inhibitor for breast cancer cells. Cancer Res 2006; 66: 10267– 10273
    1. Evans JMM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD: Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330: 1304– 1305
    1. Bowker SL, Majumdar SR, Veugelers P, Johnson JA: Increased cancer-related mortality for patients with type 2 diabetes who use sulfonylureas or insulin. Diabetes Care 2006; 29: 254– 258
    1. Moore MA, Park CB, Tsuda H: Implications of the hyperinsulinaemia-diabetes-cancer link for preventive efforts. Eur J Cancer Prev 1998; 7: 89– 107
    1. Garmendia ML, Pereira A, Alvarado ME, Atalah E: Relation between insulin resistance and breast cancer among Chilean women. Ann Epidemiol 2007; 17: 403– 409
    1. Morris AD, Boyle DIR, MacAlpine R, Emslie-Smith A, Jung RT, Newton RW, MacDonald TM: for the DARTS/MEMO Collaboration The diabetes audit and research in Tayside Scotland (DARTS) study: electronic record linkage to create a diabetes register. BMJ 1997; 315: 524– 528
    1. Evans JMM, McDevitt DG, MacDonald TM: The Tayside Medicines Monitoring Unit (MEMO): a record-linkage system for pharmacovigilance. Pharmaceut Med 1995; 9: 177– 184
    1. Information and Statistics Division Scotland Scottish Cancer Registry [Internet]. Information Services Division, NHS National Services Scotland. Available from Accessed 1 November 2008
    1. World Health Organization Manual of the International Statistical Classification of Diseases, Injuries and Causes of Death 9th revision Geneva, World Health Org., 1978
    1. World Health Organization International Statistical Classification of Diseases and Related Health Problems 10th revision Geneva, World Health Org., 1994
    1. Carstairs V: Deprivation and health in Scotland. Health Bull (Edinb) 1990; 48: 162– 175
    1. Evans JMM, Ogston SA, Emslie-Smith A, Morris AD: Risks of mortality and adverse cardiovascular outcomes in type 2 diabetes: a comparison of patients treated with sulphonylureas and metformin. Diabetologia 2006; 49: 930– 936
    1. Alessi DR, Sakamoto K, Bayascas JR: LKB1-dependent signaling pathways. Annu Rev Biochem 2006; 75: 137– 163
    1. Inoki K, Guan K-L: Complexity of the TOR signalling network. Trends Cell Biol 2006; 16: 206– 212
    1. Carling D: The role of the AMP-activated protein kinase in the regulation of energy homeostasis. Novartis Found Symp 2007; 286: 72– 81
    1. Fryer LG, Parbu-Patel A, Carling D: The anti-diabetic drugs rosiglitazone and metformin stimulate AMP-activated protein kinase through distinct signaling pathways. J Biol Chem 2002; 277: 25226– 25232
    1. Hardie DG: Minireview: the AMP-activated protein kinase cascade: the key sensor of cellular energy status. Endocrinology 2003; 144: 5179– 5183
    1. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE: Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest 2001; 108: 1167– 1174

Source: PubMed

Patrocinadores e Colaboradores

Condições médicas

Intervenções de drogas

3
Se inscrever