Dataset Information

Dose response of sodium glucose cotransporter-2 inhibitors in relation to urinary tract infections: a systematic review and network meta-analysis of randomized controlled trials.

ABSTRACT:

Background

The sodium glucose cotransporter-2 (SGLT2) inhibitors are a novel group of drugs for treatment of type 2 diabetes mellitus. We investigated whether there is a dose-response relation between SGLT2 inhibitors and urinary tract infections (UTIs) in patients with type 2 diabetes, relative to other diabetes therapies or placebo.

Methods

We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) of SGLT2 inhibitors in patients with type 2 diabetes. We searched 6 databases and the reference lists of key papers. We included studies with placebo or active antidiabetic comparators that reported the outcome of UTI, and established thresholds for high and low doses of SGLT2 inhibitors. We used a random-effects model to estimate the pooled effect estimates and 95% credible intervals.

Results

We screened 2418 citations and included 105 references for studies of 8 unique SGLT2 inhibitors, representing 60 082 individuals (with a total of 4348 UTIs). Most mixed-treatment comparisons showed no significant difference in risk of UTI, with the exception of high-dose dapagliflozin (≥ 10 mg) compared with placebo (odds ratio [OR] 1.30, 95% credible interval 1.09-1.57), with active comparators (OR 1.44, 95% credible interval 1.15-1.79), with empagliflozin at both low (OR 1.30, 95% credible interval 1.04-1.60) and high (OR 1.39, 95% credible interval 1.12-1.72) doses, and with low-dose ertugliflozin (OR 1.43, 95% credible interval 1.01-2.01). When the analysis was restricted to RCTs with a low risk of bias, the results were nonsignificant.

Interpretation

Current RCT evidence does not suggest a dose-response relation between most SGLT2 inhibitors and UTIs, with the exception of dapagliflozin. Further research is needed to quantify the relation between SGLT2 inhibitors and more serious infections.

Trial registration

PROSPERO registration no. CRD42016038715.

SUBMITTER: Donnan JR

PROVIDER: S-EPMC6287977 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background:Prior studies evaluating risk for severe urinary tract infections (UTIs) with sodium-glucose cotransporter-2 (SGLT-2) inhibitors have reported conflicting findings. Objective:To assess whether patients initiating use of SGLT-2 inhibitors were at increased risk for severe UTI events compared with those initiating use of dipeptidyl peptidase-4 (DPP-4) inhibitors or glucagon-like peptide-1 receptor (GLP-1) agonists. Design:Population-based cohort study. Setting:2 large, U.S.-based databases of commercial claims (March 2013 to September 2015). Participants:Within each database, 2 cohorts were created and matched 1:1 on propensity score. Patients were aged 18 years or older, had type 2 diabetes mellitus, and were initiating use of SGLT-2 inhibitors versus DPP-4 inhibitors (cohort 1) or GLP-1 agonists (cohort 2). Measurements:The primary outcome was a severe UTI event, defined as a hospitalization for primary UTI, sepsis with UTI, or pyelonephritis; the secondary outcome was outpatient UTI treated with antibiotics. Hazard ratios (HRs) were estimated in each propensity score-matched cohort, with adjustment for more than 90 baseline characteristics. Results:After 1:1 matching on propensity score, 123 752 patients were identified in cohort 1 and 111 978 in cohort 2 in the 2 databases. In cohort 1, persons newly receiving SGLT-2 inhibitors had 61 severe UTI events (incidence rate [IR] per 1000 person-years, 1.76), compared with 57 events in the DPP-4 inhibitor group (IR, 1.77) (HR, 0.98 [95% CI, 0.68 to 1.41]). In cohort 2, those receiving SGLT-2 inhibitors had 73 events (IR, 2.15), compared with 87 events in the GLP-1 agonist group (IR, 2.96) (HR, 0.72 [CI, 0.53 to 0.99]). Findings were robust across sensitivity analyses; within several subgroups of age, sex, and frailty; and for canagliflozin and dapagliflozin individually. In addition, SGLT-2 inhibitors were not associated with increased risk for outpatient UTIs (cohort 1: HR, 0.96 [CI, 0.89 to 1.04]; cohort 2: HR, 0.91 [CI, 0.84 to 0.99]). Limitation:Generalizability of the study findings may be limited to patients with commercial insurance. Conclusion:In a large cohort of patients seen in routine clinical practice, risk for severe and nonsevere UTI events among those initiating SGLT-2 inhibitor therapy was similar to that among patients initiating treatment with other second-line antidiabetic medications. Primary Funding Source:Brigham and Women's Hospital, Division of Pharmacoepidemiology and Pharmacoeconomics.

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