A prospective study of type 2 diabetes, metformin use, and risk of breast cancer

Ann Oncol. 2021 Mar;32(3):351-359. doi: 10.1016/j.annonc.2020.12.008. Epub 2021 Jan 29.


Background: Type 2 diabetes (T2D) has been associated with increased breast cancer risk, but commonly prescribed antidiabetic medications such as metformin may reduce risk. Few studies have investigated T2D and medications together in relation to breast cancer.

Patients and methods: Data came from 44 541 Sister Study participants aged 35 to 74 years at enrollment (2003-2009) who satisfied eligibility criteria, followed through 15 September 2017. Information on time-varying, self-reported, physician-diagnosed, prevalent and incident T2D, use of antidiabetic medications, and covariates was obtained from baseline and follow-up questionnaires. Incident breast cancers were confirmed with medical records. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated.

Results: During follow-up (median, 8.6 years), 2678 breast cancers were diagnosed at least 1 year after enrollment. There were 3227 women (7.2%) with prevalent and 2389 (5.3%) with incident T2D, among whom 61% (n = 3386) were ever treated with metformin. There was no overall association between T2D and breast cancer risk (HR 0.99; 95% CI, 0.87-1.13). However, T2D was associated with increased risk of triple-negative breast cancer (HR 1.40; 95% CI, 0.90-2.16). Compared with not having T2D, T2D with metformin use was not associated with overall breast cancer risk (HR 0.98; 95% CI, 0.83-1.15), but it was associated with decreased risk of estrogen receptor (ER)-positive breast cancer (HR 0.86; 95% CI 0.70-1.05) and increased risk of ER-negative (HR 1.25; 95% CI, 0.84-1.88) and triple-negative breast cancer (HR 1.74; 95% CI, 1.06-2.83). The inverse association with ER-positive cancer was stronger for longer duration (≥10 year) metformin use (HR 0.62; 95% CI, 0.38-1.01; P for trend = 0.09). Results were supported by sensitivity analyses.

Conclusion: Our findings suggest that associations between T2D and breast cancer may differ by hormone receptor status and that associations between T2D and ER-positive breast cancer may be reduced by long-term metformin use.

Keywords: antidiabetic medication; breast cancer; estrogen receptor; metformin; triple-negative; type 2 diabetes.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Adult
  • Aged
  • Breast Neoplasms* / epidemiology
  • Diabetes Mellitus, Type 2* / drug therapy
  • Diabetes Mellitus, Type 2* / epidemiology
  • Female
  • Humans
  • Hypoglycemic Agents / therapeutic use
  • Metformin* / therapeutic use
  • Middle Aged
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Factors


  • Hypoglycemic Agents
  • Metformin