Sodium‐glucose co‐transporter‐2 inhibitor therapy and unmasking of JAK2‐mutated myeloproliferative neoplasm: A Mayo Clinic series of nine consecutive cases

Sodium-glucose co-transporter-2 inhibitors (SGLT-2Is) referred to as “gliflozins” (canagliflozin, empagliflozin, dapagliflozin, and ertugliflozin) are FDA-approved for diabetes mellitus, heart failure, and chronic renal disease.1-3 A significant increase in hemoglobin/hematocrit (Hgb/Hct) has been consistently observed with SGLT-2I use; in a placebo-controlled study with empagliflozin versus placebo, increase in Hct was 5.0% ± 5.3% versus 0.9% ± 4.7%.4 We have previously described the benign clinical course of SGLT-2I-associated JAK2-unmutated erythrocytosis.5, 6 In the current study, we report on nine patients with previously unrecognized JAK2-mutated myeloproliferative neoplasm (MPN), in whom SGLT-2I use was associated with unmasking of their underlying MPN and manifestation of “clonal” erythrocytosis, associated with four incidents of thrombotic complications in three patients. Under an institutional review board approved research protocol, study patients were identified during a survey of cases with SGLT-2I associated erythrocytosis, seen at the Mayo Clinic (2018–2023). Patients with previously known MPN, prior to initiation of treatment with SGLT-2I, were excluded from further analysis. Erythrocytosis was defined according to the International Consensus Classification (ICC) threshold for diagnosis of polycythemia vera (PV).7, 8 Hgb/Hct level above 16.5 g/dL/49% in males and 16 g/dL/48% in females.8 Diagnosis of JAK2-mutated MPN was established through the ICC criteria.8 Study inclusion criteria included not only the absence of a formal MPN diagnosis but also absence of Hgb/Hct levels that crossed the above-mentioned thresholds for erythrocytosis, at baseline. Information abstracted from patient history included (i) baseline Hgb/Hct prior to initiation of SGLT-2I, (ii) Hgb/Hct values during therapy, and (iii) major arterial and venous thrombotic events and therapeutic interventions. A total of nine patients (median age 65 years, range 48–84; 7 males) with erythrocytosis after initiation of SGLT-2I therapy and subsequent diagnosis of JAK2-mutated MPN were studied. The majority of patients were on empagliflozin 25 mg (n = 4), empagliflozin 10 mg (n = 1) followed by dapagliflozin 10 mg (n = 3) and canagliflozin 300 mg (n = 1). A history of thrombosis prior to initiation of SGLT-2I was documented in four patients which included three arterial and one venous thrombotic event(Table 1). Additional contributors for erythrocytosis were identified in seven patients, including seven with treated obstructive sleep apnea and one with tobacco use. Baseline median values (range) for Hgb/Hct prior to SGLT2-I were 15.6 g/dL (14.1–16.3 g/dL)/47.1% (43.1%–48.3%); none of the nine patients met ICC criteria for PV, prior to initiation of therapy with SGLT-2I (Table 1). Patient 1 65 M OSA DM Dapagliflozin 10 mg 12 months MI Hgb/Hct 19/60 Plt 805 × 109/L CVA Hgb/Hct 14.8/46.2 Plt 537 × 109/L Phlebotomy Aspirin HU Ropeginterferon Ruxolitinib Patient 2 64 M PAD CAD HTN DM Dapagliflozin 10 mg 19 months PE/DVT Hgb/Hct 16.5/50.8 Plt 504 × 109/L Phlebotomy Aspirin Apixaban HU Yes 15.6/47.9 Patient 3 84 M OSA HTN DM Empagliflozin 25 mg 35 months CVA Hgb/Hct 17/50.1 Plt 143 × 109/L Phlebotomy Aspirin Patient 4 51 M DM Afib Empagliflozin 25 mg 15 months Phlebotomy Apixaban HU Yes 15/48.9 Patient 5 78 M OSA HTN DM Afib Empagliflozin 25 mg 4 months MI TIA Phlebotomy Aspirin Rivoxaraban Pegylated interferon Patient 6 59F OSA HTN DM Empagliflozin 25 mg 14 months Yes 14.2/44.9 Phlebotomy-free Patient 7 48F Smoking OSA DM Dapagliflozin 10 mg 6 months Phlebotomy Aspirin Yes 13.7/44.5 Phlebotomy-free 30 months Patient 8 66 M OSA HTN DM Afib Canagliflozin 300 mg 27 months Phlebotomy Rivoxaraban HU Patient 9 68 M OSA DM Empagliflozin 10 mg 18 months Phlebotomy Aspirin HU Subsequent to treatment with SGLT-2I (median duration 15 months; range 4–35), all nine patients experienced significant increase in their Hgb/Hct levels, crossing the ICC thresholds for diagnosis of PV. At the time of the post-SGLT-2I diagnosis of MPN, median Hgb/Hct values were 17.5 g/dL (16.2–19 g/dL)/53.1% (51.1%–60%) with median increase from baseline Hgb/Hct of 2.3 g/dL (0.4–3.2 g/dL)/7.4% (3.2%–12.7%). Erythrocytosis was accompanied by leukocytosis >10 × 109/L and thrombocytosis >450 × 109/L in seven and three patients, respectively. JAK2V617F mutation was detected in all cases and independent bone marrow morphology review was consistent with PV in patients 1–5; patients 6 and 7 demonstrated slight panhyperplasia with spectrum of megakaryocyte morphology suggestive of an evolving MPN; bone marrow biopsy was not performed in patient 8, and morphology was consistent with MPN unclassifiable (MPN-U) in patient 9 (Table 1). Median serum erythropoietin (Epo) level was 4.9 mIU/mL (range; 1.1–26.9); notably serum Epo level was subnormal in only one patient. SGLT-2I was discontinued after MPN diagnosis in four patients; serial Hgb/Hct measurements confirmed resolution of erythrocytosis in two patients (Patients 6 and 7; Table 1). At a median follow-up of 32 months (range; 21–91), since initiation of SGLT-2I, a total of four thrombotic events were documented in three patients, which included three arterial and one venous event. Notably, two of the four thrombotic events preceded the formal diagnosis MPN; with one event each at the time of and after MPN diagnosis. Hgb/Hct levels were >16.5 g/dL/45% at the time of each thrombotic event. The first patient was a 65-year-old man with baseline Hgb/Hct of 14.6 g/dL/42%, presented 1 year after initiation of dapagliflozin, with a non-ST elevation myocardial infarction and heart failure in the context of significant erythrocytosis (Hgb/Hct of 19 g/dL/60%), accompanied by leukocytosis 14.7 × 109/L, and thrombocytosis 805 × 109/L, which led to a diagnosis of PV. In addition, 4 months later while still on dapagliflozin but under treatment with phlebotomy, aspirin and hydroxyurea, he experienced acute infarction involving the right centrum semiovale with Hgb/Hct of 14.8 g/dL/46.2%, which suggested potential difficulty in Hct control in MPN patients receiving SGLT-2I. The second patient was a 64-year-old man with prior history of deep venous thrombosis, developed bilateral pulmonary embolism with right heart strain, 15 months following initiation of dapagliflozin. Hgb/Hct at the time of event and baseline were 16.5 g/dL/50.8% and 15.7 g/dL/46.2%, respectively. Further workup confirmed PV; dapagliflozin was discontinued. Subsequent treatment included aspirin, apixaban, hydroxyurea, and phlebotomy; Hct remains well-controlled since discontinuation of SGLT-2I without additional thrombosis. The third patient, an 84-year-old man, demonstrated increased Hgb/Hct of 17 g/dL/50.1% from baseline Hgb/Hct of 15.9 g/dL/47.4%, while on empagliflozin for 10 months, and suffered an acute ischemic stroke, involving the posterior right frontal lobe. Two years following cerebrovascular accident, PV was recognized (Hgb/Hct of 16.3 g/dL/52.3%); phlebotomy was implemented and empagliflozin and aspirin were continued while cytoreductive therapy was not initiated based on patient preference. The patient is currently maintained on phlebotomy. Table 1 summarizes the clinical course of all nine study patients and Figure 1 highlights the temporal relationship between SGLT-2I therapy, MPN diagnosis, and thrombotic events. The current study suggests that unmasking of an underlying MPN, in some patients receiving SGLT-2I treatment, might be associated with clonal erythrocytosis and thrombotic complications. By contrast, we have previously published on the benign nature of JAK2-unmutated erythrocytosis, induced by SGLT-2I use.5 Our observations are critical, in terms of patient safety, and flag the need for careful exclusion of an underlying MPN, in patients who develop erythrocytosis after initiation of SGLT-2I therapy. Furthermore, physicians engaged in the use of SGLT-2Is, regardless of whether or not they are hematologists, should carefully review the complete blood count, including platelet count, leukocyte count, and also pay attention to those patients with borderline increased Hgb/Hct levels, in order not to overlook masked PV; we strongly recommend screening for JAK2 mutation, when in doubt, and particularly when erythrocytosis is accompanied by leukocytosis and/or thrombocytosis9; this is easily accomplished by peripheral blood screening for JAK2 (exon 12–15) mutations. The current study also highlights the impact of SGLT-2I use on diagnosis and subtype designation of MPN, within the framework of the ICC8 and WHO classification sytems10; both employ Hgb/Hct levels to distinguish PV from JAK2-mutated essential thrombocythemia or MPN-U. Accordingly, active treatment with SGLT-2I might lead to erroneous MPN subtype designation, unless baseline Hgb/Hct levels are recalibrated after treatment discontinuation. Another important point to consider is the mechanistically recognized effect of SGLT-2I therapy on serum Epo levels, thus undermining its complementary value in the diagnosis of PV.11 Finally, our observation on the apparent provocation of thrombosis by drug-induced increase in Hct surpassing 45%, in the context of an underlying MPN, corroborates the current practice of maintaining strict Hct control of <45% in patients with PV.12 Accordingly, the decision on whether or not to continue SGLT-2I in patients with JAK2-mutated MPN should take into account the ability to achieve optimal Hct control. Naseema Gangat and Ayalew Tefferi designed the study, collected data, performed analyses, and wrote the paper. Hassan Alkhateeb provided study patients. Kaaren Reichard reviewed bone marrow biopsies. All authors reviewed the final draft of the paper. The authors declare no conflicts of interest. The data that support the findings of this study are available on request from the corresponding author.