Background: Type 2 diabetes (T2D) is a globally prevalent disease that has been associated with increased breast cancer (BC) risk thought to be linked to metabolic dysregulation. To date, however, the impact of T2D on BC-related and overall mortality remains understudied and may have important implications when designing real-world studies investigating the effects of antihyperglycemic drugs on these outcomes.
Objectives: The objective of this study is to investigate whether pre-existing T2D is associated with an increased risk of BC-related and overall mortality, compared with non-diabetes, among women newly diagnosed with non-metastatic and metastatic BC, separately.
Methods: Using the Clinical Practice Research Datalink, Hospital Episodes Statistics repository, and Office for National Statistics databases, we assembled a cohort of patients, at least 18 years of age, newly diagnosed with invasive, BC between 1998 and 2020, with follow-up until March 2021. Patients with pre-existing T2D were identified based on the presence of T2D diagnoses, use of antihyperglycemic drugs, and elevated glycemic levels. Multivariable Cox proportional hazards models including over 30 covariates (demographics, comorbidities, drugs, etc.) were fit to estimate the hazard ratios (HRs) and 95% confidence intervals (CIs) of BC mortality and overall mortality, comparing T2D to non-diabetes. In a secondary analysis, we estimated the HRs for the outcomes across glycated hemoglobin A1C (HbA1c) categories to determine how it is associated with mortality.
Results: We identified 157,298 patients with newly diagnosed BC, including 13,908 (8.8%) with T2D. Among non-metastatic patients, T2D was associated with a 12% increased risk of BC mortality (2.19 v 1.43 per 100 person years; HR: 1.12, 95% CI: 1.04 to 2.10) and a 21% increased risk of overall mortality (6.43 v 3.15 per 100 person years; HR: 1.21, 95% CI 1.16 to 1.26). Among metastatic patients, T2D was associated with a 22% increased risk of BC mortality (5.76 v 3.68 per 100 person years; HR: 1.22, 95% CI 1.11 to 1.35) and a 24% increased risk of overall mortality (9.25 v 5.20 per 100 person years; HR: 1.24, 95% CI: 1.15-1.33). The secondary analysis showed that risk of the outcomes increased with higher HbA1c in both the non-metastatic group and metastatic group.
Conclusions: In this large population-based cohort study, T2D was associated with an increased risk of BC-related and overall mortality compared with non-diabetes, with a positive linear relationship between HbA1c and these outcomes. Our findings may provide important methodological considerations for confounding by severity in future studies investigating the effects of antihyperglycemic drugs on prognostic outcomes among populations with T2D and BC.
