Hemochromatosis Gene Mutation in Persons Developing Erythrocytosis on Combined Testosterone and SGLT-2 Inhibitor Therapy

In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) use alone in persons with type 2 diabetes (T2D) or testosterone replacement therapy (TRT) prescription alone in men with hypogonadism was shown to lead to a modest but significant increase in red blood cell mass. Recent evidence indicates that combined use of TRT and SGLT-2i in persons with T2D may be associated with risk of erythrocytosis. However, factor(s) that may lead to the development of erythrocytosis in these patients is unknown. We describe here 5 consecutive patients with hypogonadism on chronic TRT who developed erythrocytosis following addition of SGLT-2i empagliflozin for optimization of T2D management. In addition to the careful review of medical history, all patients underwent genetic screening for hereditary hemochromatosis. We have found that none of the patients had C282Y mutation in the HFE (Homeostatic Iron Regulator) gene and 4 out of 5 patients had heterozygosity in the H63D allele. Upon TRT discontinuation or its dose reduction or referral for scheduled phlebotomy, patients showed resolution of erythrocytosis. Our study reaffirms that practitioners should monitor for changes in hematocrit following the initiation of SGLT-2i in persons with T2D and hypogonadism on chronic TRT. Also, for the first time, we showed that in some of the patients receiving combined TRT and SGLT-2i H63D heterozygosity in the HFE gene may mediate the development of new-onset erythrocytosis.