Review: Adding a DPP-4 inhibitor to an SGLT-2 inhibitor reduces genital, but not genitourinary, tract infections

The authors of an accompanying ACP Journal Club commentary noted that although the risk for bias in the five reviewed studies was reportedly low, the results were imprecise and inconsistent, leaving little confidence in the evidence of an apparent reduction in infection risk with dipeptidyl peptidase-4 (DPP-4) inhibitors.

A review of five randomized controlled trials (RCTs) found significantly lower risk for genital tract infections (GTIs) in patients taking dipeptidyl peptidase-4 (DPP-4) inhibitors in combination with sodium-glucose co-transporter-2 (SGLT2) inhibitors, compared to those taking SGLT2 inhibitors alone. The findings were supported by an analysis of data from the Food and Drug Administration Adverse Event Reporting System, reviewers also found.

The review was published online Oct. 20, 2017, by Diabetes, Obesity and Metabolism and appeared in the March 2018 print issue. The following commentary by René Rodriguez-Gutierrez, MD, MSc, ACP Member, and Victor M. Montori, MD, MSc, FACP, was published in the ACP Journal Club section of the March 20 Annals of Internal Medicine.

SGLT2 inhibitors may reduce risk for adverse cardiovascular outcomes. However, they have been associated with higher risk for diabetic ketoacidosis and genitourinary tract infections. The review by Fandini and colleagues found decreased risk for GTIs but no significant effect on UTIs in patients with type 2 diabetes treated with SGLT2 inhibitors plus DPP-4 inhibitors compared with SGLT2 inhibitors alone. Although the risk for bias of the summarized studies (which included open label RCTs) was reportedly low, results were imprecise (due to very few infections) and inconsistent across studies. Thus, one is left with little confidence in the evidence of an apparent reduction in the risk for infections with DPP-4 inhibitors. Even if true, we wonder how DPP-4 inhibitors protected against GTIs (given that they cannot interfere with SGLT2 inhibitor–induced glycosuria) and whether they achieved this by means other than their glucose-lowering effect, a feature common to any glucose-lowering medication (GLM). The review offers no comparison of DPP-4 inhibitors with other GLMs.

Patients and clinicians must collaborate to craft a treatment program that provides benefits that matter to patients (e.g., mortality, cardiovascular disease), while minimizing harm (including interactions with other drugs or conditions) and burden of treatment (cost, convenience, fit within the patient's daily routine). At some point, most patients with type 2 diabetes need combination drug therapy; whether DPP-4 inhibitors should be preferred over other drugs, such as metformin, to reduce the risk for SLGT2 inhibitor–associated infections remains unresolved.