Lewis Maor, Burrack Nitzan, Heymann Anthony, Grossman Alon, Neuman Tsipora, Abuhasira Ran
Department of Family Medicine, Meuhedet Health Maintenance Organization, Tel-Aviv, Israel.
Faculty of Medical and Health Sciences, Tel-Aviv University, Tel-Aviv, Israel.
JAMA Netw Open. 2025 Jun 2;8(6):e2517086. doi: 10.1001/jamanetworkopen.2025.17086.
Sodium-glucose cotransporter 2 inhibitors (SGLT2is) are widely used and have been shown to induce erythrocytosis. However, the clinical implications of this phenomenon, particularly its association with venous and arterial thrombotic events, remain uncertain.
To assess the extent, temporal course, and thrombotic complications of SGLT2i-induced erythrocytosis.
DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used patient data from Israel's largest health care organization from January 1, 2015, through June 30, 2024. Adult patients aged 18 years or older with type 2 diabetes who initiated SGLT2is were identified and compared with those who initiated dipeptidyl peptidase 4 inhibitors (DPP-4is) or glucagon-like peptide 1 receptor agonists (GLP-1RAs) using a propensity score-matched, active-comparator, new-user cohort design.
New initiation of an SGLT2i, a GLP-1RA, or a DPP-4i.
Outcomes included erythrocytosis within 1 year of initiating SGLT2is, as well as arterial and venous thrombotic events until the end of follow-up. Prevalence rates, rate differences, and odds ratios (ORs) for new-onset erythrocytosis and hemoglobin increase greater than 0.5 g/dL with 95% CIs were calculated. Hazard ratios (HRs) and 95% CIs for thrombotic outcomes were estimated using time-varying Cox proportional hazards regression models.
After 1:1 propensity score matching, a total of 137 552 adults were included in the SGLT2i vs DPP-4i cohort (68 776 pairs; SGLT2i initiators: mean [SD] age, 64.55 [12.03] years; 55.3% male; DPP-4i initiators: mean [SD] age, 64.73 [13.08] years; 53.5% male) and 131 512 adults in the SGLT2i vs GLP-1RA cohort (65 756 pairs; SGLT2i initiators: mean [SD] age, 63.73 [11.87] years; 52.0% male; GLP-1RA initiators: mean [SD] age, 62.77 [11.56] years; 51.4% female). Among SGLT2i initiators, erythrocytosis prevalence in the SGLT2i vs DPP-4i cohort increased by 5.5% (95% CI, 5.1%-5.8%) and in the SGLT2i vs GLP-1RA cohort by 5.8% (95% CI, 5.4%-6.2%). In the SGLT2i vs GLP-1RA cohort, hemoglobin increased by 0.37 g/dL (95% CI, 0.36-0.38 g/dL) and hematocrit by 1.50% (95% CI, 1.48%-1.53%). Male sex (adjusted OR [AOR], 4.12; 95% CI, 3.80-4.48), smoking (AOR, 2.00; 95% CI, 1.85-2.16), and the use of empagliflozin vs dapagliflozin (AOR, 1.16; 95% CI, 1.09-1.25) were associated with an increased risk of developing erythrocytosis. New-onset erythrocytosis was not associated with an increased risk of myocardial infarction (HR, 0.92; 95% CI, 0.58-1.44), venous thromboembolism (HR, 1.56; 95% CI, 0.68-3.60), or stroke (HR, 1.26; 95% CI, 0.84-1.90).
In this cohort study of patients with type 2 diabetes, SGLT2i use was associated with a higher risk of erythrocytosis compared with DPP-4is and GLP-1RAs; however, erythrocytosis was not associated with thrombotic events. These findings provide important reassurance regarding the safety of SGLT2i-induced erythrocytosis.
钠-葡萄糖协同转运蛋白2抑制剂（SGLT2i）被广泛使用，且已被证明可诱发红细胞增多症。然而，这一现象的临床意义，尤其是其与静脉和动脉血栓事件的关联，仍不明确。
评估SGLT2i诱发的红细胞增多症的程度、时间进程和血栓并发症。
设计、背景和参与者：这项回顾性队列研究使用了以色列最大的医疗保健机构从2015年1月1日至2024年6月30日的患者数据。确定了开始使用SGLT2i的18岁及以上2型糖尿病成年患者，并使用倾向评分匹配、活性对照、新使用者队列设计，将其与开始使用二肽基肽酶4抑制剂（DPP-4i）或胰高血糖素样肽1受体激动剂（GLP-1RA）的患者进行比较。
新开始使用SGLT2i、GLP-1RA或DPP-4i。
结局包括开始使用SGLT2i后1年内的红细胞增多症，以及直至随访结束时的动脉和静脉血栓事件。计算了新发红细胞增多症的患病率、率差和优势比（OR），以及血红蛋白增加大于0.5 g/dL时的95%置信区间。使用时变Cox比例风险回归模型估计血栓结局的风险比（HR）和95%置信区间。
在1:1倾向评分匹配后，SGLT2i与DPP-4i队列共纳入137552名成年人（68776对；SGLT2i起始者：平均[标准差]年龄，64.55[12.03]岁；男性占55.3%；DPP-4i起始者：平均[标准差]年龄，64.73[13.08]岁；男性占53.5%），SGLT2i与GLP-1RA队列共纳入131512名成年人（65756对；SGLT2i起始者：平均[标准差]年龄，63.73[11.87]岁；男性占52.0%；GLP-1RA起始者：平均[标准差]年龄，62.77[11.56]岁；女性占51.4%）。在SGLT2i起始者中，SGLT2i与DPP-4i队列的红细胞增多症患病率增加了5.5%（95%置信区间，5.1%-5.8%），SGLT2i与GLP-1RA队列增加了5.8%（95%置信区间，5.4%-6.2%）。在SGLT2i与GLP-1RA队列中，血红蛋白增加了0.37 g/dL（95%置信区间，0.36-0.38 g/dL），血细胞比容增加了1.50%（95%置信区间，1.48%-1.53%）。男性（调整后OR[AOR]，4.12；95%置信区间，3.80-4.48）、吸烟（AOR，2.00；95%置信区间，1.85-2.16）以及使用恩格列净对比达格列净（AOR，1.16；95%置信区间，1.09-1.25）与发生红细胞增多症的风险增加相关。新发红细胞增多症与心肌梗死风险增加无关（HR，0.92；95%置信区间，0.58-1.44）、静脉血栓栓塞风险增加无关（HR，1.56；95%置信区间，0.68-3.60）或中风风险增加无关（HR，1.26；95%置信区间，0.84-1.90）。
在这项2型糖尿病患者的队列研究中，与DPP-4i和GLP-1RA相比，使用SGLT2i与红细胞增多症风险较高相关；然而，红细胞增多症与血栓事件无关。这些发现为SGLT2i诱发的红细胞增多症的安全性提供了重要的 reassurance 。 （注：原文“reassurance”直译为“安心、放心”，结合语境这里可理解为“依据、保障”之类的意思，具体需根据上下文进一步确定准确含义，但按要求此处不添加解释，直接保留英文）
