Investigation and management of erythrocytosis

We thank Dr. Mithoowani and colleagues for their excellent review on the investigation and management of erythrocytosis (1), which provides a comprehensive overview and approach to a common presentation encountered by hematologists and general practitioners alike.

One additional drug-associated cause of secondary erythrocytosis of increasing relevance in general practice is the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors. With the growing use of this class of medications in Canada, on the basis of mounting evidence for improved cardiovascular outcomes in type 2 diabetes and heart failure, SGLT2 inhibitors are worth including in the already extensive differential for secondary erythrocytosis offered by Mithoowani et al. in their article (1).

At our centre, we have noted an increase in the number of referrals of patients with erythrocytosis on SGLT2 inhibitors, which often resolves following discontinuation of these medications. Increases in hematocrit were noted in initial clinical trials of SGLT2 inhibitors, and were thought to account in part for the cardioprotective effects of these medications. The physiology of SGLT2 inhibitor-induced erythrocytosis is complex and remains to be fully elucidated but postulated mechanisms include hemoconcentration, modulation of iron metabolism, and increased erythropoietin production, as recently demonstrated in a Canadian study (2).

To date, we are aware of a total of five cases of severe erythrocytosis (hematocrit >0.53) attributed to SGLT2 inhibitors reported in the literature (3-5), although anecdotally we suspect this number to be much higher and indeed rising. Two cases were associated with concomitant use of SGLT2 inhibitors and testosterone replacement therapy (4), a well-known cause of secondary erythrocytosis. Another report detailed an SGLT2 inhibitor ‘unmasking’ underlying polycythemia vera (PV) (3). To prevent over-utilization of laboratory resources, we would caution against routine investigation for PV in patients with erythrocytosis on SGLT2 inhibitors. The stepwise approach advocated by Mithoowani et al. (1) will help mitigate over-investigation. Where possible, and if alternate agents are available, we would consider discontinuing SGLT2 inhibitors in cases of severe erythrocytosis in consultation with other members of the medical team as an important diagnostic and therapeutic step in the approach to erythrocytosis.