Masked anemia and hematocrit elevation under sodium glucose transporter inhibitors: findings from a large real-world study.

AIMS: Sodium glucose transporter inhibitors (SGLT2i) therapy is associated with an increase in hematocrit as a class effect. There is a lack of information regarding the clinical magnitude and significance of hematocrit elevation, especially cardiovascular outcomes in patients with polycythemia and possible masking of lower hemoglobin levels as a sign of potential severe disease. METHODS: A retrospective study utilizing large community healthcare provider electronic database. Hematocrit levels and variables with potential effect on hematocrit change were compared before and during SGLT2i treatment in adults with type 2 diabetes mellitus. RESULTS: Study population included 9646 patients treated with Dapagliflozin or Empagliflozin between 01.2015 and 06.2019. Hematocrit levels were significantly higher after treatment initiation (2.1%), with higher median elevation among male vs female (2.3% vs. 1.8%). Anemia prevalence was significantly lower under treatment (20% vs. 31.6%). In multivariable model, gender, smoking status, SGLT2i type, pretreatment hematocrit, diabetes duration, body mass index and estimated glomerular filtration rate change significantly effected hematocrit change. CONCLUSIONS: In the current study SGLT2i treatment was associated with significant hematocrit elevation, polycythemia and lower anemia prevalence. Further studies are needed to determine the clinical significance and approach to patients with pretreatment or on treatment polycythemia and the approach to patients with lower-normal hemoglobin levels under SGLT2i treatment.

Erythrocytosis in Gender-Affirming Care With Testosterone.

PURPOSE: Gender-affirming hormone therapy (GAHT) is safe overall, with few adverse effects. One potential effect from using testosterone for GAHT is an increase in hemoglobin and/or hematocrit, known as secondary erythrocytosis. Current guidelines recommend monitoring hemoglobin or hematocrit routinely in the first year, some as frequently as every 3 months, which can create barriers to care. Our study explored the incidence of erythrocytosis in the first 20 months of testosterone therapy among people receiving gender-affirming care. METHODS: This is a descriptive fixed cohort study of hematocrit and hemoglobin data from the charts of 282 people taking testosterone for GAHT. RESULTS: During the first 20 months of testosterone therapy, the cumulative incidence of hematocrit >50.4% was 12.6%, hematocrit >52% was 1.0%, and hematocrit >54% was 0.6%. All people were taking injectable testosterone cypionate, with a median dose of 100 mg weekly. CONCLUSION: Severe erythrocytosis (hematocrit >54%) is a rare outcome of gender-affirming testosterone therapy. Clinical recommendations should reconsider the need for routine frequent erythrocytosis screening within the first year of testosterone therapy for patients who prefer to minimize laboratory draws.

Progressive erythrocytosis under lenvatinib treatment in patients with advanced hepatocellular carcinoma.

PURPOSE: This manuscript reports on the occurrence of early and frequent erythrocytosis in advanced hepatocellular carcinoma (HCC) patients treated with lenvatinib. METHODS: A cohort of 23 patients with advanced HCC, treated with this antiangiogenic drug for at least one month, was retrospectively analyzed. RESULTS: These patients (82.7% men, median age 58.3, cirrhosis in 60.8%) were treated between October 2019 and September 2020 with lenvatinib, as first-line systemic therapy for 82.6% of them. For 20 patients (87%), an early and significant increase in hemoglobin (Hb) level, up to 1.41 g/dL (p < 0.001) was reported and remained elevated. Ten patients (43.5%), all men, reached erythrocytosis (Hb > 16.5 g/dL), 7 were treated with low-dose aspirin for primary thromboprophylaxis and 2 needed phlebotomy. None underwent thromboembolic complications. A significant Hb decrease was observed after treatment discontinuation (p < 0.05). Erythropoietin (EPO) serum levels also increased, which was attributed to HCC after immunostaining for EPO in liver biopsies. The Naranjo adverse drug reaction probability scale documented the relationship between erythrocytosis and lenvatinib and regression at treatment discontinuation. Erythrocytosis was hypothesized to be a class effect of anti-VEGF therapies, the magnitude of which might depend on the IC50 value of each molecule. CONCLUSION: This report documents the frequent occurrence of erythrocytosis during lenvatinib treatment for advanced HCC, likely secondary to EPO secretion by tumor cells through the antiangiogenic activity levatinib. An early and close monitoring of hematologic parameters is, thus, recommended, together with thromboprophylaxis by low-dose aspirin and phlebotomy in case of symptomatic erythrocytosis.

Comparing Rates of Polycythemia in Hypogonadal Men Using Nasal Testosterone Gel Versus Intramuscular Testosterone: Update of a Randomized Clinical Trial.

Men with hypogonadism who use intranasal testosterone are less likely to develop polycythemia than men using intramuscular testosterone cypionate.

Incidence, Contributing Factors, and Implications for Clinical Management of Polycythemia in Transmasculine Patients on Testosterone.

Purpose: The goal of this study was to evaluate contributing factors and management strategies for polycythemia in transmasculine patients on testosterone therapy. Methods: A retrospective analysis of medical records was performed for transmasculine patients on testosterone for at least 12 months. Data collected from each patient included age, body mass index (BMI), nicotine dependence, pulmonary disease status, obstructive sleep apnea (OSA) status, oophorectomy status, and testosterone route of administration. For patients who developed polycythemia, polycythemia management strategy data were collected. Results: Five-hundred-eleven patients were evaluated and 113 (22%) experienced an episode of polycythemia. Within the polycythemia group, 77% of patients were younger than age 40, 56% had a BMI >30.0, 44% had current or former nicotine dependence, 12% had a pulmonary disease, 12% had OSA, and 47% had received an oophorectomy. The polycythemia group had a significantly higher average age, BMI, and dose of testosterone, and also had a higher proportion of patients with OSA and an oophorectomy. Conclusion: These results revealed that polycythemia is a common side effect for transmasculine patients on testosterone. Importantly, previous oophorectomy may be associated with polycythemia which appears to be a novel finding. This finding requires further research but provides the potential to be an important screening consideration for transmasculine patients after oophorectomy. Polycythemia will continue to be a major concern for patients on testosterone therapy, and this study provided important information for clinical practice and future research that will lead to improved outcomes.

Management of Erythrocytosis in Men Receiving Testosterone Therapy: Clinical Consultation Guide.

The most common side effect of testosterone therapy (TT) is erythrocytosis. Patient-specific factors therefore should be considered when choosing an appropriate TT dosage and modality. Providers should decrease or discontinue therapy if the patient's hematocrit exceeds 54% until the hematocrit normalizes.

Risk Factors for Erythrocytosis in Renal Transplantation: Is Ganciclovir Therapy One of Them?

BACKGROUND The purpose of this study was to identify the prevalence and risk factors of post-transplant erythrocytosis (PTE) and its relationship with cytomegalovirus (CMV). MATERIAL AND METHODS The study consisted of patients who received a kidney allograft and followed-up in our nephrology transplantation clinic from 2000 to 2014. Patient age, sex, length of dialysis, etiology of end-stage kidney disease, date of transplantation, medications, types of donors, the development of PTE were recorded. RESULTS Among 185 adult kidney recipients, 43 (23.2%) had PTE. The average time between transplantation and diagnosis was 36 months. PTE was more common in male patients (P<0.05) and patients with living donors and those who had been treated with ganciclovir after transplantation (P<0.05). There were 79 patients treated for CMV - 54 in the non-PTE group and 24 in the PTE group. There was no significant difference in patient age, etiology of end-stage kidney disease, and immunosuppressive therapy when comparing the PTE group and non-PTE group. Univariate analysis showed ganciclovir therapy was significantly associated with PTE. However, this was not seen in the multivariate analyses. CONCLUSIONS Treatment with ganciclovir can precipitate development of PTE. Prospective studies are needed to assess the association of between PTE and CMV infection, valganciclovir, and ganciclovir.

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.

Cardiovascular benefits of SGLT2 inhibitors in type 2 diabetes, interaction with metformin and role of erythrocytosis: a self-controlled case series study.

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have proven cardiovascular benefits in patients with type 2 diabetes (T2D). This self-controlled case series study aims to evaluate whether metformin use and SGLT2i-associated erythrocytosis influence its cardiovascular benefits. METHODS: T2D patients with metformin and/or SGLT2i prescriptions between 2015 and 2020 were identified from the Hong Kong population. Study outcomes were composite cardiovascular diseases (CVD), coronary heart disease (CHD), hospitalisation for heart failure (HHF), stroke, and erythrocytosis. Risk periods were patient-time divided into four mutually exclusive windows: (i) 'baseline period' of metformin use without SGLT2i; (ii) pre-SGLT2i period; (iii) exposure to SGLT2i without metformin; and (iv) exposure to the drug combination. Another SCCS model was applied to evaluate the association between erythrocytosis and cardiovascular outcomes regarding SGLT2i exposure. Four mutually exclusive risk periods included (i) SGLT2i exposure with erythrocytosis; (ii) SGLT2i exposure without erythrocytosis; (iii) absence of SGLT2i exposure with erythrocytosis; and (iv) absence of SGLT2i exposure without erythrocytosis. Incidence rate ratios (IRR) of events at different risk periods were estimated using conditional Poisson regression model. RESULTS: Among 20,861 patients with metformin and/or SGLT2i prescriptions, 2575 and 1700 patients with events of composite CVD and erythrocytosis were identified, respectively. Compared to metformin use without SGLT2i, SGLT2i initiation was associated with lower risks of composite CVD, CHD, and HHF-regardless of the presence (CVD: IRR = 0.43, 95% CI 0.37-0.51; CHD: IRR = 0.44, 95% CI 0.37-0.53; HHF: IRR = 0.29, 95% CI 0.22-0.40; all p < 0.001) and absence of concomitant metformin (CVD: IRR = 0.31, 95% CI 0.20-0.48; CHD: IRR = 0.38, 95% CI 0.25-0.59; HHF: IRR = 0.17, 95% CI 0.09-0.31; all p < 0.001); while SGLT2i was neutral on stroke risk. Compared to metformin-SGLT2i combination, exposure to SGLT2i alone was associated with comparable risks of all cardiovascular outcomes (all p > 0.05). Incidence rates of erythrocytosis at baseline, SGLT2i without and with metformin use periods were 0.75, 3.06 and 3.27 per 100 person-years, respectively. SGLT2i users who developed erythrocytosis had lower risk of HHF (IRR = 0.38, 95% CI 0.14-0.99, p = 0.049) than those who did not. CONCLUSIONS: Our real-world data suggested that SGLT2i-associated cardiovascular benefits were not attenuated by metformin use. Further studies will delineate the role of erythrocytosis as a surrogate marker of SGLT2i-associated cardiovascular benefit in reducing HHF.

Testosterone therapy and secondary erythrocytosis.

Secondary erythrocytosis is one of the most common adverse events associated with testosterone therapy (TT). Upon encountering this, clinicians will often either adjust TT dosing, stop therapy, order a phlebotomy, or recommend a combination of these. Despite this, the evidence for secondary polycythemia causing harm during TT is scarce, and the hematocrit-based cutoffs present in multiple guidelines appear to be arbritrarily chosen. In this review, we present the pathophysiology behind TT and secondary erythrocytosis, the evidence connecting TT, secondary erythrocytosis and major adverse cardiovascular events (MACE), and the data supporting varying interventions upon diagnosis of secondary erythrocytosis.

Secondary Polycythemia in Men Receiving Testosterone Therapy Increases Risk of Major Adverse Cardiovascular Events and Venous Thromboembolism in the First Year of Therapy.

PURPOSE: An unsafe hematocrit threshold for men receiving testosterone therapy (TT) has never been tested. This study seeks to determine whether secondary polycythemia among men receiving TT confers an increased risk of major adverse cardiovascular events (MACE) and venous thromboembolic events (VTE). MATERIALS AND METHODS: Using a multi-institutional database of 74 million patients, we identified 2 cohorts of men with low testosterone (total testosterone <350 ng/dl) who received TT and subsequently either developed polycythemia (5,887) or did not (4,2784). Polycythemia was defined as hematocrit ≥52%. As a secondary objective, we identified 2 cohorts of hypogonadal men without polycythemia, who either did (26,880) or did not (27,430) receive TT. Our primary outcome was the incidence of MACE and VTE in the first year after starting TT. We conducted a Kaplan-Meier survival analysis to assess differences in MACE and VTE survival time, and measured associations following propensity score matching. RESULTS: A total of 5,842 men who received TT and developed polycythemia were matched and compared to 5,842 men who did not develop polycythemia. Men with polycythemia had a higher risk of MACE/VTE (number of outcomes: 301, 5.15%) than men who had normal hematocrit (226, 3.87%) while on TT (OR 1.35, 95% CI 1.13-1.61, p <0.001). In hypogonadal men who received testosterone, no increased risk of MACE and VTE was identified as compared to hypogonadal men naïve to TT. CONCLUSIONS: Developing polycythemia while on TT is an independent risk factor for MACE and VTE in the first year of therapy. Future research on the safety of TT should include hematocrit as an independent variable.

Prospective study on blood pressure, lipid metabolism and erythrocytosis during and after androgen abuse.

Androgen abuse is associated with unfavourable changes in blood pressure, lipid metabolism and erythrocytosis. Most knowledge is based on cross-sectional studies sensitive to bias. We assessed the magnitude of these effects and their recovery in a prospective cohort study which included 100 men (≥18 years) performing an androgen cycle. Clinic visits took place before the cycle, at the end, 3 months after and 1 year after start of the cycle and included measurement of blood pressure, lipid parameters and haematocrit. During androgen use, systolic and diastolic blood pressure increased 6.87 (95% CI 4.34-9.40) and 3.17 mmHg (1.29-5.04) compared to baseline respectively. LDL cholesterol and ApoB increased 0.45 mmol/L (0.29-0.61) and 18.2 mg/dl (13.5-22.8) respectively, whereas HDL cholesterol, ApoA and Lp(a) decreased with 0.40 mmol/L (-0.45 to 0.35), 36.6 mg/dl (30.2-42.9) and 37.6% (13.9-61.3). ANGPTL3 increased 20.3% (7.38-33.2). Mean haematocrit increased 0.03 L/L (0.02-0.03). Three months after the cycle, and 1 year after the start, these parameters returned to baseline. In conclusion, androgen abuse induces small but clinically relevant adverse changes in blood pressure, lipid metabolism and erythrocytosis which are rapidly reversible after cessation. As follow-up was limited to 1 year, the impact of androgen abuse on cardiovascular disease remains uncertain.

Sustained erythrocytosis due to the use of Lenvatinib.

INTRODUCTION: Tyrosine kinase inhibitors have become the mainstay of treatment for many malignancies, but their use can be accompanied by unusual and often puzzling side effects. CASE REPORT: We describe herein a 64-year-old patient who developed a robust and sustained erythrocytosis shortly after starting treatment with lenvatinib. Our patient also experienced elevated blood pressure, mucositis, and hand-foot syndrome that are not uncommonly seen with this agent. The clinico-laboratory work-up suggested that lenvatinib was the likely culprit in this case. MANAGEMENT & OUTCOME: Lenvatinib had to be discontinued due to suboptimal tolerance and a short-lived response. With the discontinuation of lenvatinib, hemoglobin trended downwards and subsequently resolved. A score of 6 on the Naranjo nomogram supported a probable causality relationship between lenvatinib and the observed erythrocytosis. DISCUSSION: Erythrocytosis has previously been described with sunitinub, sorafenib and pazopanib. The exact mechanism of this phenomenon is not known. It might increase the risk of venous and arterial thromboses in cancer patients that are already in a hypercoagulable state due to cancer itself. In addition, laboratory work-up for polycythemia may prove extensive and costly. Therefore, clinicians need to be aware of this important side effect of tyrosine kinase inhibitors.

UNUSUAL CAUSE OF BRANCH RETINAL ARTERY OCCLUSION: POLYCYTHEMIA IN A TRANSGENDER MAN FROM UNREGULATED TESTOSTERONE USE.

PURPOSE: We report a transgender patient with branch retinal artery occlusion who had secondary polycythemia from unregulated testosterone injections and review the literature on the mechanisms of supraphysiologic and standard doses of testosterone causing a hypercoagulable state. METHODS: Case report. RESULTS: A 45-year-old Chinese transgender man with no medical history presented with a 1-week history of a scotoma in his left eye vision. Ophthalmologic examination revealed retinal pallor and edema along the superotemporal arteriole in the left eye. Optical coherence tomography showed increased thickness of the inner retinal layers of the superotemporal retina. Fluorescein angiography demonstrated an arm-retina time of 1 minute and 43 seconds, with no vascular sheathing and capillary fallout. A diagnosis of left superotemporal branch retinal artery occlusion was made. Initial blood tests revealed a hemoglobin level of 19.3 g/dL (11.8-14.6 g/dL), hematocrit of 62% (34.3-43.0%), and erythrocytes of 6.56 × 1012/L (3.7-4.8 × 1012/L). He revealed later that he had been on weekly testosterone injections (testosterone enanthate 250-mg depot injection) since 2011. He was also exposed to a moderately high altitude, when his symptoms occurred, raising the possibility of worsening hypercoagulability resulting in his thrombotic event. CONCLUSION: To the best of our knowledge, this is the first documented case of a trans man who developed branch retinal artery occlusion after self-administering supraphysiological doses of testosterone. In a young patient with no history of cardiovascular risk factors who develops retinal arterial occlusion, other causes such as hypercoagulable syndromes must be excluded. This case warns of the dangers of unregulated testosterone use, especially at supraphysiologic doses, and the risks of thrombotic events from secondary polycythemia.