Abstract
<title>Abstract</title> <p>Background and Aims Sodium-glucose cotransporter-2 inhibitors (SGLT2i), initially approved for type 2 diabetes mellitus, have progressively emerged as cardio-renal protective agents. Beyond glycaemic control, evidence indicates that SGLT2i act as systemic endocrine-metabolic modulators, via pleiotropic mechanisms including NLRP3 inflammasome inhibition, ketone-driven metabolic reprogramming, HIF-2α-mediated erythropoietic effects, and uricosuric transporter activity. This scoping review maps Real-World Data (RWD)-based evidence on SGLT2i repositioning across these pathways and rare diseases. Methods A systematic search was conducted on PubMed and Scopus from inception to 31 May 2026, following PRISMA-ScR guidelines (OSF registration: 10.17605/OSF.IO/794CX). Eligibility followed a PCC framework (Population: any age/comorbidity; Concept: pleiotropic or off-label SGLT2i effects beyond approved cardio-renal indications; Context: real-world studies). Original peer-reviewed studies using RWD, including cohort studies and case series for rare diseases, were included. Methodological quality was assessed using the Newcastle-Ottawa Scale (NOS) and the Murad et al. tool. Due to clinical and methodological heterogeneity, a narrative synthesis was performed. Results Seventy-four studies (2017–2026) were included, 66% published in 2024–2026. Research was concentrated in Asia (27 studies, NHIRD-based) and North America (24 studies, mainly EHR/TriNetX-based), with Europe contributing 16 studies. Seven thematic clusters were identified. Gout showed the most robust evidence (19 studies; median NOS 7; 30–50% risk reduction), driven by a uricosuric transporter-mediated mechanism. Anaemia (10 studies; +0.7–1.0 g/dL haemoglobin increase; up to 64% reduction in erythropoiesis-stimulating agents) showed signals consistent with genuine erythropoietic stimulation rather than haemoconcentration. Rare metabolic-transport diseases (13 studies; median Murad score 7), including glycogen storage disease type 1b and Fanconi-Bickel syndrome, represented a context where RWD provided the only available evidence, including off-label empagliflozin use in 21 infants with GSD type 1b. COPD (9 studies; 19–38% exacerbation reduction), neuroprotection, hepatoprotection and oncology showed promising but preliminary signals. Haemoglobin normalisation potentially masking underlying pathologies ("masked anaemia") may warrant specific monitoring. Conclusions RWD-based evidence supports progressive repositioning of SGLT2i as systemic endocrine-metabolic agents, with gout and anaemia approaching guideline-level maturity. Methodological evolution towards Target Trial Emulation has strengthened observational inference. Future priorities include multicontinental data integration, standardised lag periods and active comparators, and enhanced clinical vigilance to prevent biochemical improvement from obscuring underlying diagnoses.</p>