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UTI risk not raised with SGLT-2is in real-world study

Pearl Toh
17 Sep 2019

The use of SGLT-2* inhibitors was not associated with a higher risk of severe or nonsevere urinary tract infections (UTIs) in patients with type 2 diabetes (T2D) compared with DPP**-4 inhibitors or GLP-1*** receptor agonists, a population-based cohort study shows.

There was no increase in the primary outcome of severe UTI events# (61 vs 57) among patients initiating SGLT-2 inhibitors compared with those who initiated DPP-4 inhibitors (incidence rate [IR] per 1,000 person-years, 1.76 vs 1.77, hazard ratio [HR], 0.98, 95 percent confidence interval [CI], 0.68–1.41). [Ann Intern Med 2019;doi:10.7326/M18-3136]

Similarly, initiating SGLT-2 inhibitors was not associated with an elevated risk of severe UTI events compared with GLP-1 receptor agonists (73 vs 87 events, IR, 2.15 vs 2.96, HR, 0.72, 95 percent CI, 0.53–0.99).

“Although SGLT-2 inhibitors have consistently been shown to increase risk for genital infections, their association with UTIs is less clear,” according to the researchers. “In 2015, the US FDA revised labels for all SGLT-2 inhibitors to add a warning about severe UTIs … prompted by postmarketing reports of sepsis with UTI and pyelonephritis in patients using these agents.”

“[The study] provides encouraging evidence of the real-world safety of SGLT-2 inhibitors, allowing patients to benefit from their use with greater confidence in their safety with respect to severe UTI,” wrote Drs Kristian Filion and Oriana Yu from McGill University in Montreal, Canada in an accompanying editorial. [Ann Intern Med 2019;doi:10.7326/M19-1950]

The large population-based study compared T2D patients who initiated the use of SGLT-2 inhibitors vs DPP-4 inhibitors in one cohort (n=123,752), or vs GLP-1 receptor agonists in another cohort (n=111,978) using databases of healthcare claims in the US.

The findings that severe UTI events were similar among the groups receiving SGLT-2 inhibitors, DPP-4 inhibitors, and GLP-1 receptor agonists persisted across sensitivity and subgroup analyses, regardless of age, sex, and frailty.

Specifically, the results did not differ when analysing separate drugs in the SGLT-2 inhibitor class. Neither canagliflozin nor dapagliflozin was associated with increased UTI events (HRs, 0.83, 95 percent CI, 0.57–1.21 and 0.57, 95 percent CI, 0.29–1.14, respectively) when compared with DPP-4 inhibitors or compared with GLP-1 receptor agonists (HRs, 0.66, 95 percent CI, 0.47–0.92 and 0.52, 95 percent CI, 0.28–0.97, respectively).

Also, there were no significant associations between SGLT-2 inhibitors and risk of outpatient UTIs (HR, 0.96, 95 percent CI, 0.89–1.04 vs DPP-4 inhibitors and HR, 0.91, 95 percent CI, 0.84–0.99 vs GLP-1 receptor agonists).

According to the researchers, the findings hold important clinical implications, given that “patients with diabetes have a higher frequency and severity of UTIs, [and] thus, antidiabetic agents that increase [the] risk for such infections may decrease quality of life, predisposing patients to therapy discontinuation and poor glycaemic control.”

The findings are also consistent with a recent meta-analysis of 72 trials showing no elevated risk of severe or nonsevere UTI events with SGLT-2 inhibitors. [Acta Diabetol 2018;55:503-514]

“On the basis of our findings, other factors beyond risk for UTI events should be considered in decisions about whether to prescribe SGLT-2 [inhibitor] therapy for patients with diabetes in routine care settings,” they concluded.

While the study provides reassuring, real-world evidence, Filion and Yu noted that this comes with some caveats. “First, the study excluded high-risk patients and those with a history of UTI, key subgroups for which further evidence is needed.”

The researchers also cautioned against generalizing the results to other populations, such as older adults who might be more susceptible to severe UTI events.


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