The risk of genito-urinary infections with sodium-glucose cotransporter-2 inhibitors: duration rather than dose matter?

KEYWORDS:

• Sodium-glucose cotransporter-2 inhibitors
• adverse reaction
• urinary tract infection
• genital infection
• duration

We read with great interest the well-conducted article by Sridharan et al. [1], which enrolled 264 articles for the evaluation of the risk of urinary tract infection (UTI) and genital infection (GI) with sodium-glucose cotransporter-2 inhibitors (SGLT2is) through systematic review and meta-analysis. The study reported that SGLT2is increased the risk of UTI (Odd ratios [OR] 1.11, 95% confidence interval (CI) 1.06 to 1.16) and GI (OR 3.5, 95% CI 3.1 to 3.9) compared to placebo/standard of care. These findings are aligned to our previous article of systematic review and meta-analysis [2], which extracted non-diabetic data from randomized clinical trials of 8927 patients with heart failure or chronic kidney disease, demonstrated that SGLT2is increased the risk of UTI (risk ratios [RR] 1.29, 95% CI 1.05 to 1.58) and GI (RR 2.44, 95% CI 1.14 to 5.25) compared with placebo. Furthermore, another systematic review also reported an increased risk of UTI and GI associated with SGLT2is [3].

In contrast to the above, there has been controversy regarding the risk of UTI associated with SGLT2is, whereas the association between SGLT2is and GI has been consistently demonstrated. In a meta-analysis of 77 clinical trials conducted by Liu et al. [4], there was an increased risk of GI with SGLT2is (RR 3.30, 95% CI 2.74 to 3.99) but no difference in the rate of UTI (RR 1.05, 95% CI 0.98 to 1.12) compared to control. A similar finding was noted in a meta-analysis of 68 clinical trials conducted by Puckrin et al. [5], which reported that SGLT2is are associated with an increased risk of GI (RR 3.37, 95% CI 2.89 to 3.93) but there was no overall association between SGLT2is and UTI (RR 1.08, 95% CI 0.93 to 1.25).

The inconsistent results among available studies regarding the relationship between SGLT2is and the risk of UTI may be partially explained by differences in the study duration of follow-up. As pointed out by Fralick et al. [6], some trials of SGLT2is with a longer duration of follow-up did detect an increased risk of UTI with SGLT2is. Our previous systematic review [2] and the other systematic review [3] all included studies of SGLT2is with a longer trial duration (i.e. more than 1 year) and detected an increased risk of UTI with SGLT2is. In addition, the study by Zheng et al. showed that dapagliflozin with a longer treatment period (i.e. >24 weeks) was associated with a higher risk of UTI than placebo or other active treatments [7]. It has been hypothesized that increased urinary flow caused by SGLT2is attenuates over time, which may result in UTI during long-term treatment with SGLT2is [6].

Notably, there was consistent evidence that longer duration of SGLT2is treatment increased the risk of GI. The meta-regression analyses by Sridharan et al. [1] revealed that studies with a longer duration of SGLT2is treatment (i.e. >6 months) increased the risk of GI. This finding is supported by the study of Liu et al. [4], which also reported an association between longer length of follow-up and increased risk of GI with SGLT2is.

Given the variation in the rate of urinary glucose excretion with different doses of individual SGLT2is, a dose – response relation is another plausible issue regarding the association between the risk of genito-urinary infection and SGLT2is. In the study by Zheng et al. [7], an increased risk of UTI was observed with dapagliflozin at high doses (10 mg/day). This finding, however, is not supported by the result of the network meta-analysis by Sridharan et al. [1] or the study by Donnan et al. [8]. Further studies are needed to examine the effect of dose on the relationship between SGLT2is and genito-urinary infection.

Although evidence suggested that SGLT2is increased the risk of UTI and GI, the incidence of these adverse events was consistently low. As the cardiorenal benefits of SGLT2is outweighed the risk of genito-urinary infection, concerns regarding the heightened risk of genito-urinary infection should not be a barrier to their prescription. Strategies like shared decision-making may facilitate broader adoption of these medications.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.