Metformin Use and Leukemia Risk in Patients With Type 2 Diabetes Mellitus

BACKGROUND: The effect of metformin on leukemia risk remains unknown. METHODS: The Taiwan’s National Health Insurance database was used to enroll 610,089 newly diagnosed type 2 diabetes patients on at least 2 anti-diabetic prescriptions during 1999–2009. We followed-up these patients until 31 December 2011, in order to determine the incidence of leukemia. We used Cox regression model (incorporated with the inverse probability of treatment-weighting using propensity scores) to estimate hazard ratios in both intention-to-treat and per-protocol analyses. RESULTS: We enrolled 414,783 metformin initiators and 195,306 non-metformin initiators. Among them, 598 and 372 patients developed new-onset leukemia after a median follow-up period of 5.08 years and 6.79 years, respectively. The respective incidence rates were 26.52 and 28.40 per 100,000 person-years. The hazard ratio for metformin initiators versus non-metformin initiators was 0.943 (95% confidence interval 0.828–1.074) in the intention-to-treat analysis and 0.852 (95% confidence interval 0.705–1.031) in the per-protocol analysis. Sensitivity analyses after excluding patients using the exclusion criteria (a follow-up duration < 24 and < 36 months, respectively, patients with incretin-based therapies during follow-up, and patients enrolled during 2 different periods of 1999–2003 and 2004–2009) consistently showed a neutral effect. However, metformin initiators had a significantly higher risk of leukemia in the per-protocol analyses when censoring patients at a time without regular follow-up. CONCLUSION: Metformin use has an overall neutral effect on leukemia but we cannot exclude a significantly higher risk in patients who persistently use the drug.