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Introduction Sodium-glucose cotransporter-2 (SGLT2) inhibitors were originally introduced for glycaemic management of type 2 diabetes mellitus and now provide substantial cardiovascular and kidney benefits. Although their association with genital mycotic infections is well established, whether SGLT2 inhibitor initiation increases the risk of symptomatic urinary tract infections (UTIs) remains uncertain, particularly within the cardiovascular-kidney-metabolic syndrome framework. This protocol describes a prospective multicentre observational study designed to address this clinically important uncertainty in a Chinese population with complex multimorbidity.Methods and analysis This is a prospective, multicentre, observational cohort study conducted between June 2026 and June 2028 at two tertiary hospitals in China. Adults newly initiating an SGLT2 inhibitor or a clinically appropriate non-SGLT2 active comparator will be enrolled. A new-user design and 1:1 propensity score matching will be used to reduce confounding by indication and prevalent-user bias. A total of 2400 participants (1200 per group) will be recruited. The primary endpoint is the first newly onset symptomatic UTI during 12 months of follow-up, defined by prespecified clinical symptoms plus laboratory evidence. Clinician-diagnosed genital infection is retained as a secondary safety endpoint. The primary treatment–effect estimate will be obtained using a Cox proportional hazards model in the matched cohort with cluster-robust SEs. Absolute cumulative incidence will be estimated with the Aalen-Johansen method, and Fine-Gray regression will provide a complementary competing-risk analysis for all-cause mortality. Sensitivity analyses will address treatment switching, stricter culture-confirmed outcomes, missing covariates and unmeasured confounding.Ethics and dissemination The study protocol and informed consent documents have been reviewed and approved by the Clinical Research Ethics Committees of Qilu Hospital (Qingdao), Shandong University and the Second Affiliated Hospital of Xi'an Jiaotong University (Approval No. KYLL-2025100). The study will be conducted in accordance with the Declaration of Helsinki, ICH-GCP and ISPE Good Pharmacoepidemiology Practices. Written informed consent will be obtained from all participants prior to enrolment. Findings will be disseminated through peer-reviewed publications and academic conferences, regardless of whether results are positive, negative or inconclusive.Trial registration number Chinese Clinical Trial Registry (ChiCTR), registration number ChiCTR2600124776; registered prior to first participant enrolment.