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

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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 

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

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 

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

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 

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 

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 

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 

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