Dipeptidyl peptidase-4 inhibitors moderate the risk of genitourinary tract infections associated with sodium-glucose co-transporter-2 inhibitors

Genitourinary tract infections (GUTIs) are the most common adverse event (AE) occurring during therapy with sodium-glucose co-transporter-2 (SGLT2) inhibitors. We evaluated whether dipeptidyl peptidase-4 inhibitors moderate the risk of GUTI during SGLT2 inhibitor therapy, using two approaches. First, we screened the literature for randomized controlled trials (RCTs) directly comparing the frequency of GUTIs in patients receiving DPP-4 inhibitor/SGLT2 inhibitor combination therapy vs those receiving an SGLT2 inhibitor only. In the five trials we retrieved, the pooled risk ratio for genital tract infections (GTIs) in patients on DPP-4 inhibitor/SGLT2 inhibitor combination therapy vs those on SGLT2 inhibitors alone was 0.51 (95% confidence interval [CI] 0.28-0.92). Second, we found that within the Food and Drug Administration AE Reporting System, the frequency of GUTIs among reports listing both SGLT2 and DPP-4 inhibitors as suspect or concomitant drugs was significantly lower than among reports listing SGLT2 inhibitors without DPP-4 inhibitors, with a proportional reporting ratio of 0.74 (95% CI 0.61-0.90). In conclusion, in RCTs and in a large pharmacovigilance database, combination therapy with a DPP-4 inhibitor appears to reduce the frequency of G(U)TIs associated with SGLT2 inhibitors.