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Status: OngoingResearch Proposal
Project Title: Prediction of Urinary Tract Infection Risk Using Urinary Dipstick Tests and Assessment of Their Impact on SGLT2 Inhibitors
Scientific Abstract:
Background: Urinary tract infections (UTIs) are a frequent complication in patients with type 2 diabetes mellitus (T2DM), posing significant clinical and economic challenges. While leukocyte esterase (LE) and nitrite (NIT) dipstick tests are effective diagnostic tools for UTIs, their predictive value for UTI development remains unclear. Abnormal LE and NIT results, which indicate potential bacterial presence, may influence SGLT2 inhibitor-associated UTI risk.
Objective: To investigate whether dipstick parameters (LE and NIT) predict UTI development and evaluate their impact on SGLT2 inhibitor-related UTI risk.
Study Design: Individual participant data meta-analysis of the CANVAS Program and CREDENCE trial
Participants: Participants with T2DM at high risk of cardiovascular disease (as in the CANVAS Program) and chronic kidney disease (as in the CREDENCE trial), with dipstick test results available at baseline
Primary and Secondary Outcome Measures: Primary: Time to first UTI event. Secondary: Total UTI events.
Exploratory: Time to first genital mycotic infection.
Statistical Analysis:
The relationship between LE/NIT test results and clinical outcomes will be analyzed using univariate and multivariate Cox models for time-to-first-event analysis and the Andersen-Gill model for total events analysis. Treatment heterogeneity across multiple LE/NIT categories or binary classifications (normal vs. abnormal) will be assessed by incorporating an interaction term between these categories and treatment into both the Cox model and the Andersen-Gill model.
Brief Project Background and Statement of Project Significance:
UTIs are a prevalent condition with substantial clinical and economic consequences, particularly among patients with T2DM. Asymptomatic bacteriuria has been identified as a potential biomarker for predicting UTI incidence; however, its use in routine clinical practice is limited due to the requirement for urine culture testing. In contrast, dipstick tests, which are inexpensive and rapid, are frequently employed as initial screening methods for the detection of albuminuria and the screening of kidney diseases (Ann Intern Med. 2024 Nov;177(11):1593-1595). Despite their widespread use, the parameters of LE and NIT, which are effective diagnostic tools for UTIs, are typically overlooked when testing asymptomatic patients. The potential role of these parameters in predicting future UTI development remains uncertain. If additional clinical utility, such as predicting UTI risk, can be established for LE and NIT tests, it would provide substantial clinical benefits and improve the relevance of dipstick testing, particularly in diabetes care.
Sodium-glucose cotransporter-2 inhibitors (SGLT2i) are pivotal in the management of T2DM, heart failure, and chronic kidney disease, offering significant renal and cardiovascular protective benefits (J Am Coll Cardiol. 2022;79(17):e263-e421, Diabetes Care. 2024;47(Suppl 1):S158-s178, Kidney Int. 2024 Apr;105(4S):S117-S314). However, their mechanism of action, which involves promoting glucose excretion into the urine, raises concerns about an increased risk of UTIs. Previous studies have yielded mixed results regarding whether SGLT2i increase UTI incidence (J Clin Endocrinol Metab. 2021 Jun 16;106(7):2133-2145, BMJ Open 2019;9:e022577, Ann Intern Med. 2019 Aug 20;171(4):248-256). This uncertainty is particularly concerning for patients at high risk of developing UTIs, as the potential adverse effect could limit the clinical utility of these agents and deprive such patients of their considerable protective benefits. Determining whether SGLT2i increase UTI risk in high-risk populations is critical for guiding clinical decision-making and optimizing patient care.
To address these gaps, this study leverages datasets from the CANVAS Program (N Engl J Med 2017;377:644-57) and CREDENCE trials (N Engl J Med 2019;380:2295-306)--double-blind, placebo-controlled studies evaluating the efficacy and safety of SGLT2 inhibitors in patients with T2DM. Specifically, the study aims to (1) assess whether dipstick parameters, LE and NIT, can serve as biomarkers for predicting future UTI development, and (2) evaluate the impact of LE and NIT results, which suggest the presence of bacteria, on the development of UTIs provoked by SGLT2i will be evaluated.
Specific Aims of the Project:
Study objectives:
To evaluate whether dipstick LE and NIT results predict UTI development and whether these parameters influence UTI risks caused by SGLT2i.
Specific Hypotheses:
1. LE and NIT tests predict UTI incidence.
2. LE and NIT tests predict total UTI events.
3. Abnormal LE and NIT results increase the risk of UTI after SGLT2i initiation
Study Design: Meta-analysis (analysis of multiple trials together)
What is the purpose of the analysis being proposed? Please select all that apply.: New research question to examine treatment safety Participant-level data meta-analysis Meta-analysis using only data from the YODA Project
Software Used: STATA
Data Source and Inclusion/Exclusion Criteria to be used to define the patient sample for your study: We will conduct a pooled data analysis using individual participant data from the CANVAS Program and the CREDENCE trial. The CANVAS Program enrolled individuals with T2DM and an HbA1c of 7.0%--10.5%, aged >=30 years with a history of atherosclerotic vascular disease, or aged >=50 years with at least two cardiovascular risk factors. The CREDENCE trial included participants with T2DM and an HbA1c of 6.5%--12.0%, aged >=30 years, with an estimated glomerular filtration rate (eGFR) of 30 to <90 mL/min/1.73 m^2, a urinary albumin-to-creatinine ratio (UACR) of 300--5000 mg/g, and on renin-angiotensin system blockade therapy. Participants without baseline dipstick test results will be excluded from the analysis.
Primary and Secondary Outcome Measure(s) and how they will be categorized/defined for your study:
The primary outcome will be a time to first UTI event.
The secondary outcome will be total UTI events.
The exploratory outcome will be a time to first mycotic genital infections
These outcomes will be defined based on the pre-specified MedDRA Preferred Terms outlined in the CREDENCE trial. For these outcomes, datasets used in existing studies on UTIs will be utilized if they are made available.
Main Predictor/Independent Variable and how it will be categorized/defined for your study: The LE results of "negative" and "trace" will be interpreted as normal, whereas results of "1+," "2+," and "3+" will be classified as abnormal. Similarly, nitrite results of "negative" and "trace" will be regarded as normal, while "1+," "2+," and "3+" will be considered abnormal.
Other Variables of Interest that will be used in your analysis and how they will be categorized/defined for your study: None
Statistical Analysis Plan:
We plan to use individual participant data from the CANVAS Program and CREDENCE trial. We will use the chi-square test for categorical variables and Mann--Whitney test for continuous variables to compare baseline characteristics of patients according to the LE/NIT categories. For time to first UTI event, a multivariable Cox model was used to evaluate the association between LE/NIT categories and clinical outcomes, adjusted for age, sex, treatment (canagliflozin vs. placebo), race, history of cerebrovascular disease, diabetes duration, body mass index, glycated hemoglobin, eGFR, UACR, diuretic use, and insulin use. Covariates for the multivariable model were selected based on clinical knowledge and data availability. The effect of canagliflozin on clinical outcomes will be analyzed using a Cox model, and effect modification by the LE/NIT categories at baseline will be tested by adding two-way interaction terms between treatment and baseline LE/NIT categories. For total UTI events, the analysis will be conducted using an Andersen-Gill model following the same methodology as described above. In addition, mixed-effects logistic regression models will be employed to evaluate the effects of canagliflozin versus placebo on the serial changes in binary LE/NIT results (categorized as normal or abnormal). These models will include fixed effects for treatment and baseline LE/NIT categories, along with random intercepts to account for intra-individual variability. All statistical tests will be two-tailed, and p-values <0.05 will be considered statistically significant, whereas P <0.05 will indicate statistical significance for interactions. No adjustment will be made for multiplicity.
Narrative Summary: Urinary tract infection (UTI) is a common condition with substantial clinical and economic impact. While leukocyte esterase (LE) and nitrite (NIT) tests in dipstick urinalysis are effective for UTI diagnosis, their role in predicting UTI development remains uncertain. If their predictive utility is established, these inexpensive and rapid tests could offer significant clinical value. SGLT2 inhibitors (SGLT2i), widely used in cardiorenal-metabolic syndrome, may increase UTI risk, leading to under-prescription and limiting patients' cardiorenal benefits. This study will assess whether LE/NIT test-stratified UTI risk modifies SGLT2i's effect on UTI incidence, focusing on high-risk UTI patients.
Project Timeline: We are ready to conduct the proposed research. The analyses will be completed within 6 months. We will spend another 6 months writing (and subsequently submitting) the manuscript.
Dissemination Plan: Impressive and meaningful results were expected to be shared with healthcare providers. We plan to submit to top internal medicine or diabetes journals, such as JAMA Internal Medicine, Annals of Internal Medicine, or Diabetes Care.
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