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Sodium-Glucose Cotransporter 2 Inhibitors and Genital Mycotic Infections

Angela Kaucher, PharmD

PGY1 Pharmacy Resident, North Kansas City Hospital

Kathryn Holt, PharmD, BCPS

Clinical Assistant Professor, UMKC School of Pharmacy

          With the latest cardiovascular outcome clinical trials (CVOT) results, it is recommended patients with diabetes and established atherosclerotic cardiovascular disease (ASCVD) or risk factors for cardiovascular disease (CVD) receive anti-diabetic agents with proven CVD benefits.  Some of these agents include certain sodium-glucose cotransporter 2 inhibitors (SGLT2i) or glucagon-like peptide 1 receptor agonists (GLP-1 RA).¹ Additionally, some SGLT2i have evidence of demonstrated reductions in heart failure and chronic kidney disease (CKD) progression.¹ With a greater number of patients being initiated on SGLT2i, it is possible healthcare providers may receive more questions related to management of the potential adverse effects of SGLT2i. 

            SGLT2i, including canaglifozin, dapagliflozin, empagliflozin, and ertugliflozin, exert their pharmacological effects by inhibition of the sodium-glucose cotransporter 2 (SGLT2) located in the proximal renal tubules.² Inhibition of the SGLT2 leads to decreased reabsorption of filtered glucose and subsequent increase in urinary excretion of glucose.² Based on this mechanism, SGLT2i carry a warning for increased risk of genital mycotic infections, including vulvovaginal mycotic infection, vulvovaginal candidiasis, vulvovaginitis, candida balanitis, and balanoposthitis.

            In the major CVOTs, the risk of genital infections was increased in patients receiving SGLT2is canaglifozin, empaglifozin, and dapagliflozin compared to placebo, 68.8% vs. 17.5% (p<0.001), 6.4% vs. 1.8%, and 0.9% vs. 0.1% (p<0.001), respectively.^3,4,5 The proposed mechanism for increased risk of genital fungal infections has been linked to the increase in urinary glucose excretion (UGE) seen with SGLT2i.⁶ It is proposed increased UGE supplies glucose as a nutritional factor, thus promoting fungal growth on genital tissue and colonization which subsequently increases the risk for symptomatic infection.⁶

A study by Thong and colleagues examined possible risk factors associated with development of genital fungal infections in patients receiving SGLT2i therapy. The study examined data from 1049 patients treated with dapagliflozin. One or more treatment emergent genital fungal infection was reported in 7.8% of patients, with >95% occurring by week 18 (range 13-26) of treatment initiation and 2.4% leading to permanent discontinuation of dapagliflozin.⁷ The study found female sex and previous genital fungal infection within the last year to be associated with a statistically significant increased risk of occurrence of genital fungal infections.⁷

            In a retrospective cohort study by Gadzhanova and colleagues, SGLT2i (N=1977) use was associated with a significantly increased risk of genital infections compared to dipeptidyl peptidase 4 inhibitor (N=1964) use, 2.9% vs. 0.9%, adjusted hazards ratio 3.5, 95% CI 1.95-5.89.⁸ The infections commonly occurred during the first 12 weeks of treatment (83%) and were usually a single occurrence (91%) that responded to standard oral and topical antifungal therapies. ⁸

            The Infectious Diseases Society of America’s (IDSA) 2016 updated guideline on the management of candidiasis recommends use of topical antifungal agents or oral fluconazole 150 mg one time for the treatment of uncomplicated Candida vulvovaginitis.⁹ The guidelines give no preference to which topical antifungal agent should be used as data for superiority of one agent is lacking.⁹ Available over the counter topical options include clotrimazole 1% cream, clotrimazole 2% cream, miconazole 2% cream, miconazole 4% cream, and tioconazole 6.5% ointment. Prescription options include butoconazole 2% cream, terconazole 0.4% cream, and terconazole 0.8% cream.¹⁰ Azole-containing regimens demonstrate efficacy in 80-90% of patients who complete therapy.¹⁰ Severe Candida vulvovaginitis should be treated with oral fluconazole 150 mg every 72 hours for 2 or 3 doses.⁹ Recurrent vulvovaginal candidiasis, ≥4 infections in one year, requires acute initial treatment followed by maintenance treatment for 6 months. Initial therapy can either be topical antifungal agents for 7-14 days or oral fluconazole every 72 hours for a total of 3 doses, on days 1, 4, and 7, with maintenance therapy including oral fluconazole once weekly.^9,10 Candida balanitis is recommended to be treated with topical clotrimazole 1% cream or miconazole 2% cream twice daily until symptoms resolve.¹¹ Alternately, for severe symptoms, oral fluconazole 150 mg for one dose is recommended.¹¹

            With more patients initiated on SGLT2i, it is important to recognize which patients may be at an increased risk for adverse events including genital mycotic infections. Members of the multidisciplinary team should screen patients prior to initiation of SGLT2i for history of genital fungal infections as these patients may benefit from thorough education on the signs and symptoms of infections, including itching, vaginal soreness, dyspareunia, abnormal vaginal discharge, and external dysuria and when to seek treatment or additional medical advice.^7,10

References

1. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care 2019; 42(Supp1): S1-S193. 
2. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. c2019. [cited 2019 April 14]. Available from http://www.clinicalpharmacology.com
3. Neal B, Perkovic V, Mahaffey KW, et al. Canagliflozine and cardiovascular and renal events in type 2 diabetes. N Engl J Med 2017;377:644-57.
4. Zinman B, Wanner C, Lachin JM, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.
5. Wiviott SD, Raz I, Bonaca MP, et al. Dapagliflozin and cardiovascular outcomes in type 2 diabetes. N Engl J Med 2019:389:347-57.
6. Nyirjesy P, Sobel JD, Fung A, et al. Genital mycotic infections with canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus: a pooled analysis of clinical studies. Current Medical Research and Opinion 2014; 30(6):1109-19.
7. Thong KY, Yadagiri M, Barnes DJ. Clinical risk factors predicting genital fungal infections with sodium-glucose cotransport 2 inhibitor treatment: the ABCD nationwide dapagliflozin audit. Primary Care Diabetes 2018;12:45-50.
8. Gadzhanova S, Pratt N, Roughead E. Use of SGLT2 inhibitors for diabetes and risk of infection: analysis using general practice records from the NPS medicinewise medicineinsight program. Diabetes Research and Clinical Practice 2017;130:180-85.
9. Pappas PG, Kauffman CA, Andes DR, et al. Clinical practice guideline for the management of candidiasis: 2016 update by the infectious diseases society of America. Clin Infec Dis 2016;62(4):e1-e50.
10. Centers for Disease Control and Prevention. “Vulvovaginal Candidiasis” https://www.cdc.gov/std/tg2015/candidiasis.htm. Accessed April 14, 2019.
11. Edwards SK, Bunker CB, Ziller F, van der Meijden W. 2013 European guideline for the management of balanoposthitis. International Journal of STD &AIDS 2014; 25(9):615-626.