Hereditary Hemochromatosis Gene Mutation in Patients Developing Erythrocytosis on Combined Testosterone Replacement and SGLT-2 Inhibitor Therapy: A Case Series

Recent reports have demonstrated that male patients with type 2 diabetes (T2D) and hypogonadism receiving combined testosterone replacement therapy (TRT) and sodium-glucose cotransporter-2 inhibitor (SGLT2i) prescription may be at increased risk for erythrocytosis (E). We investigated if the incident E is associated with pathogenic mutation in common HFE genes known to result in hereditary hemochromatosis (HH).

Case Description:

Case 1: A 65-yo non-smoker white male (WM) with T2D, hypogonadism, and treated obstructive sleep apnea (OSA) received testosterone cypionate injections 150 mg bi-weekly. Empagliflozin 10mg daily was added to aid T2D control. During 3-month follow up, his hematocrit (Hct) increased from 45.0% (normal 38-50%) to 53.1%; he was advised to increase hydration and continue OSA treatment and empagliflozin was increased to 25mg daily. Nine months later, his Hct was 55.8%; empagliflozin was stopped as he opted to continue TRT that resulted in Hct normalization. Screening for HH was positive for a single H63D gene and negative for C282Y gene mutation.

Case 2: A 74-yo non-smoker WM with T2D and hypogonadism and no OSA history was on a stable regimen of topical testosterone 1.62% 20.25 mg/pump at 4 pumps daily when he was started on empagliflozin 10mg daily. Three months following empagliflozin initiation, his Hct increased from 43.4% to 49.3%; he was advised to increase empagliflozin to 25mg daily. In 6 months, he continued TRT and empagliflozin as prescribed as his Hct was stable. In 18 months since empagliflozin initiation, routine evaluation showed Hct of 56.1%. Following the discussion with the patient, he chose to reduce TRT to 2 pumps daily while continuing empagliflozin 25mg daily. One month later, repeat Hct was 47.2%. Screening for HH was positive for a single H63D gene and negative for C282Y gene mutation.

Case 3: A 72-yo WM with T2D and hypogonadism and no OSA history was on testosterone cypionate injections 150 mg bi-weekly when he was started on empagliflozin 10mg daily. Three months following empagliflozin initiation, his Hct increased from 49.0% to 56.5%. Screening for HH was positive for a single H63D gene and negative for C282Y gene mutation. Following the discussion with the patient, he was referred to hematology clinic as he chose to perform monthly therapeutic phlebotomies to maintain Hct below 50%.

Discussion:

For the first time, we report that patients who develop E while on both TRT and SGLT2i may have underlying heterozygosity in the H63D variant of the HFE gene. While TRT de-intensification or SGLT2i discontinuation will resolve E, we suggest that such patients can be offered screening for HH to expand E mitigation options as therapeutic phlebotomy can be considered if mutation(s) in HFE gene is detected.