Skip to main content
SpringerLink
Log in

Increased risk of erythrocytosis in men with type 2 diabetes treated with combined sodium-glucose cotransporter-2 inhibitor and testosterone replacement therapy

  • Original Article
  • Published:
Journal of Endocrinological Investigation Aims and scope Submit manuscript

Abstract

Purpose

In clinical trials, sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and testosterone replacement therapy (TRT) were shown to stimulate red blood cell production. Little is known if combination therapy poses risk of erythrocytosis in real world clinical practice.

Methods

This was a retrospective nationwide cohort study of US Veterans with type 2 diabetes (T2D) and baseline hematocrit between 38 and 50% who were prescribed SGLT-2i and/or TRT between 3/2013 and 10/2022 and had adequate adherence based on the proportion of days covered > 80%. Patients were divided into 3 groups: SGLT-2i only, TRT only, or combination therapy. Odds Ratio (OR) of new erythrocytosis defined as hematocrit level > 54% within 365 days of therapy initiation was calculated by logistic regression model adjusted for baseline hematocrit, age, BMI, obstructive sleep apnea, diuretic use, and smoking status.

Results

Of the entire cohort of 53,971 people with T2D, total of 756 (1.4%) patients developed erythrocytosis. In unadjusted analyses, the OR of new onset erythrocytosis was higher in the combined SGLT-2i and TRT group compared with the SGLT-2i or TRT group alone (4.99, 95% CI (3.10–7.71) and 2.91, 95% CI (1.87–4.31), respectively). In the models adjusted for baseline characteristics, patients on combination therapy had significantly higher odds of erythrocytosis compared to those on SGLT-2i (OR 3.80, 95% CI (2.27–6.11)) or TRT alone (OR 2.49, 95% CI (1.51–3.59)). Testosterone delivery route (topical vs injectable) did not modify increased odds of erythrocytosis.

Conclusions

For the first time, we demonstrated that in large cohort of patients combined therapy with SGLT-2i and TRT is associated with increased erythrocytosis risk compared with either treatment alone. Given rising prevalence of SGLT-2i use, providers should consider periodic hematocrit assessment in persons receiving both SGLT-2i and TRT.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

References

  1. Inzucchi SE, Zinman B, Fitchett D, Wanner C, Ferrannini E, Schumacher M, Schmoor C, Ohneberg K, Johansen OE, George JT, Hantel S, Bluhmki E, Lachin JM (2018) How does empagliflozin reduce cardiovascular mortality? Insights from a mediation analysis of the EMPA-REG OUTCOME trial. Diabetes Care 41:356–363

    Article  CAS  PubMed  Google Scholar 

  2. Kolkailah AA, Wiviott SD, Raz I, Murphy SA, Mosenzon O, Bhatt DL, Leiter LA, Wilding JPH, Gause-Nilsson I, Sabatine MS, McGuire DK (2022) Effect of dapagliflozin on hematocrit in patients with type 2 diabetes at high cardiovascular risk: observations from DECLARE-TIMI 58. Diabetes Care 45:e27–e29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sano M, Goto S (2019) Possible mechanism of hematocrit elevation by sodium glucose cotransporter 2 inhibitors and associated beneficial renal and cardiovascular effects. Circulation 139:1985–1987

    Article  CAS  PubMed  Google Scholar 

  4. Ghanim H, Abuaysheh S, Hejna J, Green K, Batra M, Makdissi A, Chaudhuri A, Dandona P (2020) Dapagliflozin suppresses hepcidin and increases erythropoiesis. J Clin Endocrinol Metab. https://doi.org/10.1210/clinem/dgaa057

    Article  PubMed  Google Scholar 

  5. Griffin M, Rao VS, Ivey-Miranda J, Fleming J, Mahoney D, Maulion C, Suda N, Siwakoti K, Ahmad T, Jacoby D, Riello R, Bellumkonda L, Cox Z, Collins S, Jeon S, Turner JM, Wilson FP, Butler J, Inzucchi SE, Testani JM (2020) Empagliflozin in heart failure: diuretic and cardiorenal effects. Circulation 142:1028–1039

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Mazer CD, Hare GMT, Connelly PW, Gilbert RE, Shehata N, Quan A, Teoh H, Leiter LA, Zinman B, Juni P, Zuo F, Mistry N, Thorpe KE, Goldenberg RM, Yan AT, Connelly KA, Verma S (2020) Effect of empagliflozin on erythropoietin levels, iron stores, and red blood cell morphology in patients with type 2 diabetes mellitus and coronary artery disease. Circulation 141:704–707

    Article  PubMed  Google Scholar 

  7. McMurray JJV, Solomon SD, Inzucchi SE, Kober L, Kosiborod MN, Martinez FA, Ponikowski P, Sabatine MS, Anand IS, Belohlavek J, Bohm M, Chiang CE, Chopra VK, de Boer RA, Desai AS, Diez M, Drozdz J, Dukat A, Ge J, Howlett JG, Katova T, Kitakaze M, Ljungman CEA, Merkely B, Nicolau JC, O’Meara E, Petrie MC, Vinh PN, Schou M, Tereshchenko S, Verma S, Held C, DeMets DL, Docherty KF, Jhund PS, Bengtsson O, Sjostrand M, Langkilde AM, Committees D-HT, Investigators (2019) Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med 381:1995–2008

    Article  CAS  PubMed  Google Scholar 

  8. Das L, Bhansali A, Walia R (2018) Unmasking and aggravation of polycythemia vera by canagliflozin. Diabet Med 35:1613–1616

    Article  CAS  PubMed  Google Scholar 

  9. Gangat N, Szuber N, Alkhateeb H, Al-Kali A, Pardanani A, Tefferi A (2021) JAK2 wild-type erythrocytosis associated with sodium-glucose cotransporter 2 inhibitor therapy. Blood 138:2886–2889

    Article  CAS  PubMed  Google Scholar 

  10. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, Snyder PJ, Swerdloff RS, Wu FC, Yialamas MA (2018) Testosterone therapy in men with hypogonadism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 103:1715–1744

    Article  PubMed  Google Scholar 

  11. Dhindsa S, Ghanim H, Batra M, Kuhadiya ND, Abuaysheh S, Sandhu S, Green K, Makdissi A, Hejna J, Chaudhuri A, Punyanitya M, Dandona P (2016) Insulin Resistance and inflammation in hypogonadotropic hypogonadism and their reduction after testosterone replacement in men with type 2 diabetes. Diabetes Care 39:82–91

    Article  CAS  PubMed  Google Scholar 

  12. Fernandez-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, Agrwal N, Elamin MB, Gallegos-Orozco JF, Wang AT, Erwin PJ, Bhasin S, Montori VM (2010) Clinical review 1: adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab 95:2560–2575

    Article  CAS  PubMed  Google Scholar 

  13. Roy CN, Snyder PJ, Stephens-Shields AJ, Artz AS, Bhasin S, Cohen HJ, Farrar JT, Gill TM, Zeldow B, Cella D, Barrett-Connor E, Cauley JA, Crandall JP, Cunningham GR, Ensrud KE, Lewis CE, Matsumoto AM, Molitch ME, Pahor M, Swerdloff RS, Cifelli D, Hou X, Resnick SM, Walston JD, Anton S, Basaria S, Diem SJ, Wang C, Schrier SL, Ellenberg SS (2017) association of testosterone levels with anemia in older men: a controlled clinical trial. JAMA Intern Med 177:480–490

    Article  PubMed  PubMed Central  Google Scholar 

  14. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, Gill TM, Barrett-Connor E, Swerdloff RS, Wang C, Ensrud KE, Lewis CE, Farrar JT, Cella D, Rosen RC, Pahor M, Crandall JP, Molitch ME, Resnick SM, Budoff M, Mohler ER 3rd, Wenger NK, Cohen HJ, Schrier S, Keaveny TM, Kopperdahl D, Lee D, Cifelli D, Ellenberg SS (2018) Lessons from the testosterone trials. Endocr Rev 39:369–386

    Article  PubMed  PubMed Central  Google Scholar 

  15. Snyder PJ, Peachey H, Hannoush P, Berlin JA, Loh L, Holmes JH, Dlewati A, Staley J, Santanna J, Kapoor SC, Attie MF, Haddad JG Jr, Strom BL (1999) Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab 84:1966–1972

    CAS  PubMed  Google Scholar 

  16. Corona G, Cucinotta D, Di Lorenzo G, Ferlin A, Giagulli VA, Gnessi L, Isidori AM, Maiorino MI, Miserendino P, Murrone A, Pivonello R, Rochira V, Sangiorgi GM, Stagno G, Foresta C, Lenzi A, Maggi M, Jannini EA (2023) The italian society of andrology and sexual medicine (SIAMS), along with ten other Italian Scientific Societies, guidelines on the diagnosis and management of erectile dysfunction. J Endocrinol Invest 46:1241–1274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Isidori AM, Aversa A, Calogero A, Ferlin A, Francavilla S, Lanfranco F, Pivonello R, Rochira V, Corona G, Maggi M (2022) Adult- and late-onset male hypogonadism: the clinical practice guidelines of the Italian society of andrology and sexual medicine (SIAMS) and the Italian society of endocrinology (SIE). J Endocrinol Invest 45:2385–2403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Motta G, Zavattaro M, Romeo F, Lanfranco F, Broglio F (2019) Risk of Erythrocytosis during concomitant testosterone and sglt2-inhibitor treatment: a warning from two clinical cases. J Clin Endocrinol Metab 104:819–822

    Article  PubMed  Google Scholar 

  19. Schumacher KA, Gosmanov AR (2022) Hemochromatosis gene mutation in persons developing erythrocytosis on combined testosterone and sglt-2 inhibitor therapy. J Investig Med High Impact Case Rep 10:23247096221111776

    PubMed  PubMed Central  Google Scholar 

  20. Gagnon DR, Zhang TJ, Brand FN, Kannel WB (1994) Hematocrit and the risk of cardiovascular disease–the framingham study: a 34-year follow-up. Am Heart J 127:674–682

    Article  CAS  PubMed  Google Scholar 

  21. Kunnas T, Solakivi T, Huuskonen K, Kalela A, Renko J, Nikkari ST (2009) Hematocrit and the risk of coronary heart disease mortality in the TAMRISK study, a 28-year follow-up. Prev Med 49:45–47

    Article  CAS  PubMed  Google Scholar 

  22. Canfield SL, Zuckerman A, Anguiano RH, Jolly JA, DeClercq J, Wascher M, Choi L, Knox S, Mitchell DG (2019) Navigating the Wild West of Medication Adherence Reporting in Specialty Pharmacy. J Manag Care Spec Pharm 25:1073–1077

    PubMed  Google Scholar 

  23. VA Informatics and Computing Infrastructure (VINCI), VA ORD 22-D4V, U.S. Department of Veterans Affairs. (2008). https://vincicentral.vinci.med.va.gov. Accessed 1 Oct 2022

  24. Gosmanov AR, Gemoets DE, Kaminsky LS, Kovesdy CP, Gosmanova EO (2021) Efficacy of metformin monotherapy in US veterans with type 2 diabetes and preexisting chronic kidney disease stage 3. Diabetes Obes Metab 23:1879–1885

    Article  CAS  PubMed  Google Scholar 

  25. R Core Team (2019) A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org.

  26. Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J (2004) Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306:2090–2093

    Article  CAS  PubMed  Google Scholar 

  27. Bachman E, Travison TG, Basaria S, Davda MN, Guo W, Li M, Connor Westfall J, Bae H, Gordeuk V, Bhasin S (2014) Testosterone induces erythrocytosis via increased erythropoietin and suppressed hepcidin: evidence for a new erythropoietin/hemoglobin set point. J Gerontol A Biol Sci Med Sci 69:725–735

    Article  CAS  PubMed  Google Scholar 

  28. Dhindsa S, Ghanim H, Batra M, Kuhadiya ND, Abuaysheh S, Green K, Makdissi A, Chaudhuri A, Dandona P (2016) Effect of testosterone on hepcidin, ferroportin, ferritin and iron binding capacity in patients with hypogonadotropic hypogonadism and type 2 diabetes. Clin Endocrinol (Oxf) 85:772–780

    Article  CAS  PubMed  Google Scholar 

  29. Latour C, Kautz L, Besson-Fournier C, Island ML, Canonne-Hergaux F, Loreal O, Ganz T, Coppin H, Roth MP (2014) Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin. Hepatology 59:683–694

    Article  CAS  PubMed  Google Scholar 

  30. Lambers Heerspink HJ, de Zeeuw D, Wie L, Leslie B, List J (2013) Dapagliflozin a glucose-regulating drug with diuretic properties in subjects with type 2 diabetes. Diabetes Obes Metab 15:853–862

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This material is the result of work supported with resources and the use of facilities at the Stratton VAMC, Albany, NY. Authors would like to thank Csaba Kovesdy, MD, Evan Kujawski, PharmD, Verina Mansour, PharmD, and Maria Green, DO for helpful comments.

Funding

None.

Author information

Authors and Affiliations

  1. Section of Endocrinology, Stratton VA Medical Center, 113 Holland Ave, Albany, 12208, USA

    A. R. Gosmanov

  2. Division of Endocrinology, Department of Medicine, Albany Medical College, Albany, NY, USA

    A. R. Gosmanov

  3. Department of Research and Development, Stratton VA Medical Center, Albany, NY, USA

    D. E. Gemoets

  4. Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA

    K. A. Schumacher

Authors
  1. A. R. Gosmanov
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. E. Gemoets
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. K. A. Schumacher
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.R.G. contributed to the study design, cohort development, data interpretation and wrote the manuscript. D.E.G. and K.A.S. analyzed data, contributed to the discussion and reviewed/edited the manuscript. All authors participated in drafting the article and revising it critically for important intellectual content. All authors provided their approval of this version of the manuscript for publication. A.R.G. is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Corresponding author

Correspondence to A. R. Gosmanov.

Ethics declarations

Conflict of interest

A.R.G. and D.E.G. are employees of the US Department of Veterans Affairs and their opinions expressed in this paper are those of the authors` and do not represent the views of the Department of Veterans Affairs or the US Government. A.R.G. received research support from AbbVie and KOWA Research Institute paid to the institution outside of the scope of the manuscript. The other authors declare no competing interests.

Ethical approval

This study was approved by the IRB of Stratton VAMC, Albany, NY.

Informed consent

The Institutional Review Board approved this human research study with waiver of informed consent form collection due to analyses of existing patient record.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gosmanov, A.R., Gemoets, D.E. & Schumacher, K.A. Increased risk of erythrocytosis in men with type 2 diabetes treated with combined sodium-glucose cotransporter-2 inhibitor and testosterone replacement therapy. J Endocrinol Invest (2024). https://doi.org/10.1007/s40618-024-02350-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s40618-024-02350-1

Keywords

Search

Navigation