Comparative risk of genital infections associated with sodium‐glucose co‐transporter‐2 inhibitors

Abstract

The extent to which sodium-glucose co-transporter-2 (SGLT2) inhibitors increase the risk of genital infections in routine clinical care, compared with other antidiabetic medications, is not clear, or whether the increased risk is consistent across gender or age subgroups, within individual SGLT2 agents, or if it is more pronounced at a particular time after treatment initiation. We conducted a retrospective cohort study using two US commercial claims databases (2013-2017). In the primary analysis, 1:1 propensity score-matched cohorts of female and male subjects with type 2 diabetes mellitus initiating SGLT2 versus dipeptidyl peptidase-4 inhibitors were created. The outcome was a composite of genital candidal infections, vaginitis or vulvovaginitis in women, and genital candidal infections, balanitis, balanoposthitis, phimosis or paraphimosis in men. Among propensity score-matched cohorts of 129 994 women and 156 074 men, the adjusted hazard ratio (HR) and excess risk per 1000 person-years for SGLT2 versus DPP-4 inhibitors was 2.81 (95% confidence interval [CI], 2.64, 2.99) and 87.4 (95% CI, 79.1, 96.2) respectively for women, and was 2.68 (95% CI, 2.31, 3.11) and 11.9 (95% CI, 9.3-15.0) for men. Findings were similar in the SGLT2 inhibitor versus GLP-1 agonist comparison, more pronounced in the subgroup of patients aged ≥60 (HR, 4.45 [95% CI, 3.83-5.17] in women and 3.30 [95% CI, 2.56-4.25] in men), and no meaningful difference across individual SGLT2 inhibitors was identified. This increase in risk was evident in the first month of treatment initiation and remained elevated throughout the course of therapy. SGLT2 inhibitors were associated with an approximately 3-fold increase in risk of genital infections.

A hypothesis for why sodium glucose co‐transporter 2 inhibitors have been found to cause genital infection, but not urinary tract infection

“…Nearly identical results have been found in observational studies (Table ) . For example, in the study by Dave et al, diagnostic codes specific to yeast infections caused by Candida were used and they observed a nearly threefold higher rate of genital infection among adults who received an SGLT2 …”

“…A recent meta‐analysis, including 56 clinical trials confirmed this observation, and found that SGLT2 inhibitors were associated with a threefold higher risk ratio [RR = 3.30, 95% confidence interval (CI) 2.74, 3.99, I 2 = 22%] for genital infection, regardless of sex, compared with placebo or other classes of diabetes medications . Nearly identical results have been found in observational studies (Table ) . For example, in the study by Dave et al, diagnostic codes specific to yeast infections caused by Candida were used and they observed a nearly threefold higher rate of genital infection among adults who received an SGLT2 …”

“…In this population, they reduce the risk of renal failure, heart failure, myocardial infarction, cardiovascular mortality and, potentially, all‐cause mortality . However, they are associated with clinically important adverse events, including diabetic ketoacidosis, volume depletion and genital infection . Because SGLT2 inhibitors result in marked glycosuria, it was anticipated that SGLT2 inhibitors might also cause urinary tract infection (UTI) .…”

A safety update on sodium glucose co‐transporter 2 inhibitors

“…In the phase 3 cardiovascular safety trials, genital infections occured with a 3‐ to 4‐fold increased incidence in patients receiving an SGLT2 inhibitor compared to placebo. A systematic analysis indicated a 3‐fold increased risk of developing a genital mycotic infection when receiving an SGLT2 inhibitor compared to other glucose lowering agents, with a similar incidence across individual SGLT2 inhibitors . A retrospective study of patients in a family practice setting indicated that SGLT2 inhibitors were associated with a more than 3‐fold increased risk of mycotic genital infections compared to patients receiving DPP4 inhibitors (2.9% vs 0.9%; HR 3.50; 95% CI: 1.95‐5.89).…”

Fournier's gangrene and sodium–glucose cotransporter 2 inhibitors: Is there a causal association?

“…Given these data, is SGLT2i use actually associated with FG? Although SGLT2i are associated with genital fungal infections in both women and men, 16,17 none of the reviewed studies found an association between such superficial infections and FG, which, rather, was associated with procedures such as hemorrhoidectomy and with deep space infections, such as perianal 14 or vulvar abscess, 13 so a mechanism whereby SGLT2i may cause FG is not apparent. Certainly diabetes is present in many people with FG.…”