Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Front Endocrinol (Lausanne). 2020 Oct 22;11:541090. doi: 10.3389/fendo.2020.541090. eCollection 2020.
The effect of metformin on leukemia risk remains unknown.
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.
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.
Metformin use has an overall neutral effect on leukemia but we cannot exclude a significantly higher risk in patients who persistently use the drug.
二甲双胍对白血病风险的影响尚不清楚。
本研究使用台湾全民健康保险数据库，纳入 1999-2009 年期间至少接受 2 种抗糖尿病药物治疗的 610089 例新诊断的 2 型糖尿病患者。我们对这些患者进行随访，直至 2011 年 12 月 31 日，以确定白血病的发生率。我们使用 Cox 回归模型（结合倾向评分的逆概率治疗加权），在意向治疗和方案分析中估计风险比。
我们纳入了 414783 例二甲双胍起始治疗者和 195306 例非二甲双胍起始治疗者。在中位随访时间为 5.08 年和 6.79 年后，分别有 598 例和 372 例患者发生新发白血病。相应的发生率分别为 26.52 和 28.40/100000 人年。意向治疗分析中，二甲双胍起始治疗者与非二甲双胍起始治疗者的风险比为 0.943（95%置信区间 0.828-1.074），方案分析中为 0.852（95%置信区间 0.705-1.031）。排除符合以下排除标准的患者（分别随访时间<24 个月和<36 个月、随访期间使用肠促胰岛素治疗的患者、以及分别纳入 1999-2003 年和 2004-2009 年两个不同时期的患者）后进行敏感性分析，结果仍显示中性效应。然而，当在无定期随访的时间点对患者进行删失时，二甲双胍起始治疗者在方案分析中发生白血病的风险显著更高。
二甲双胍的使用对白血病总体上无影响，但我们不能排除持续使用该药的患者发生白血病的风险显著更高。
