SGLT2 Inhibitors and Diabetes: Double Trouble for Genital Mycotic Infections

July 1, 2015

Patients with diabetes may already be at increased risk for genital mycotic infections. We look at the likelihood of infection with SGLT2 inhibitors.

Patients with diabetes may already be at increased risk for genital mycotic infections. Type 2 diabetes (T2DM) is associated with an increased risk for asymptomatic bacteriuria, urinary tract infections, balanitis, vulvovaginal infections, acute pyelonephitris, and bacteremia. Glucosuria, increased bacterial adherence to uroepithelium, and immune dysfunction may all play roles. Candida albicans has a glucose-inducible protein that facilitates yeast adhesion to genital epithelium and interferes with immune phagocytosis.

Dapagliflozin (dapa) - Authors analyzed 12 double-blind controlled clinical trials. Patients with T2DM were treated with dapa 2.5-10 mg/day for up to 24 weeks. Most infections occurred within the first 24 weeks, and recurrent infections were uncommonPatients with past history of recurrent genital infections were more likely to develop subsequent infections (dapa 5 mg: 23.1%; dapa 10 mg: 25%; placebo: 10%)6 (6.5%) and 3 (4.5%) patients on dapa 5 mg and dapa 10 mg, respectively, had inadequate response to initial treatment and needed further medication.0-0.2% of patients on dapa had to interrupt or discontinue treatment.

Women developed genital mycotic infections more frequently than men on dapa. Geerlings S, et al. Genital and urinary tract infections in diabetes: impact of pharmacologically-induced glucosuria. Diabetes Res Clin Pract. 2014 Mar;103(3):373-381. See abstract here.

Canagliflozin (cana) - Authors analyzed four placebo-controlled clinical trials (n= 2313; mean exposure cana 24.3 and placebo 23.8 months); and eight placebo-controlled studies (n=9439; mean exposure cana 68.1 and placebo 64.4 months).Most infections developed within the first four months in women and first year in men.21.5% of women and 21.9% of men in the combined cana group experienced more than one genital mycotic infection.Men who developed genital mycotic infections were more likely to have a history of balanitis/balanoposthitis (25% vs 2.3%), live in Europe (43.8% vs 26%), and be uncircumcised (5.7% vs 0.7%), compared to men who did not.Majority were treated with and responded to standard antifungals.About 1% discontinued treatment due to genital mycotic infections.

Women developed genital mycotic infections more frequently than men on cana. Nyirjesy P, 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. Curr Med Res Opin. 2014 Jun;30(6):1109-1119. See abstract here.

Empagliflozin - The newest FDA-approved SGLT2 inhibitor on the market does not have as much clinical data available.In a Phase IIb clinical trial of 408 patients, (randomized to empagliflozin 5, 10 or 25âmg once daily, placebo, or open-label metformin for 12âweeks):2% (n=5) of patients on empagliflozin developed genital infections vs. 0% on placebo.No genital infections led to premature discontinuation.In a placebo-controlled trial of 495 patients inadequately controlled on metformin (randomized to 1, 5, 10, 25, or 50âmg empagliflozin, placebo, or open-label 100 mg sitagliptin, added to metformin for 12âweeks): Only patients who received empagliflozin developed genital infections (4.0%).Ferrannini E, et al. A Phase IIb, randomized, placebo-controlled study of the SGLT2 inhibitor empagliflozin in patients with type 2 diabetes. Diabetes Obes Metab. 2013 Aug;15(8):721-728. See abstract here. Rosenstock J, et al. Efficacy and safety of empagliflozin, a sodium glucose cotransporter 2 (SGLT2) inhibitor, as add-on to metformin in type 2 diabetes with mild hyperglycaemia. Diabetes Obes Metab. 2013 Dec;15(12):1154-1160. See abstract here.

Take Home Points - Up to 10-11% of patients on SGLT2 inhibitors will experience genital mycotic infections.Most infections respond to standard antifungals, but up to 20% of patients on SGLT2 inhibitors will develop recurrent genital mycotic infections.Women are at highest risk.Uncircumcised men may be at increased risk, compared to circumcised men.All patients, regardless of sex, should be educated about the risk of genital mycotic infections when on SGLT2 inhibitors.