Mechanisms of SGLT inhibitor action and physiological mediators: systematic review and protocol for the MOSAIC collaborative meta-analysis

Kugathasan L, Nardone M, Muskiet MH, Diaz Martinez JP, Lovblom LE, Orchanian-Cheff A, Nielsen S, Rotbain V, Kazup A, Cersosimo E, Gullaksen S, Vernstrom L, van Baar MJ, van Bommel E, Kannenkeril D, Scholtes R, Hesp A, Mosterd C, Touw DJ, Lambers Heerspink H, Krebbe M, Joles J, Kvitne K, Laugesen E, Mose F, Mårup FH, Nieuwdorp M, Geist B, Maruyama S, Kato S, Kalambokis G, Tsiakas I, Jensen J, Schou M, Omar M, Kistorp CM, Perna A, Ruggenenti P, Persson F, Schmieder R, Singh S, van Raalte DH, Cherney D, Srinivasan Sridhar V (2026)

Publication Type: Journal article

Publication year: 2026

Journal

Book Volume: 16

Pages Range: e108946-

Journal Issue: 2

DOI: 10.1136/bmjopen-2025-108946

Abstract

INTRODUCTION: Sodium-glucose cotransporter (SGLT) inhibitors have shown substantial benefit in reducing cardiovascular and kidney events across diverse clinical populations, but the underlying physiological mechanisms remain unclear. However, existing mechanistic studies on renal and cardiovascular haemodynamics show variability in design, have limited statistical power and yield inconsistent outcomes, thus limiting the ability to draw generalisable conclusions. To address this gap, we conducted a systematic review and proposed the first meta-analysis to aggregate individual participant-level data from mechanistic studies to identify consistent physiological patterns and enhance understanding of the therapeutic effects of SGLT inhibition. METHODS AND ANALYSIS: Gold-standard measured glomerular filtration rate (mGFR) was selected as the primary outcome for this systematic review, which aimed to identify all completed mechanistic studies investigating the effects of SGLT inhibition. Electronic databases including Ovid MEDLINE; Ovid Embase; Cochrane Database of Systematic Reviews; and Cochrane Central Register of Controlled Trials were searched using a detailed search strategy. In total, 24 studies (n=1296) were identified. This systematic review was reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Key variables including demographics, medical history, concomitant medications, vital signs, mGFR, renal haemodynamics, urine and plasma biochemistry, tubular sodium handling, echocardiography, cardiac output monitoring, arterial stiffness and fluid volume will be extracted. A one-stage individual participant data meta-analysis under a Bayesian framework will be conducted, using hierarchical models to simultaneously analyse data from all eligible studies. The risk of bias due to missing results will be assessed. Sensitivity analyses and subgroup evaluations will be incorporated to explore sources of heterogeneity and assess robustness of findings. ETHICS AND DISSEMINATION: Ethics approval was obtained from University Health Network, Toronto, Canada. Findings from the Mechanisms of SGLT Inhibitor Action and Physiological Mediators (MOSAIC) meta-analysis will be published in peer-reviewed journals and results will be disseminated at scientific conferences. PROSPERO REGISTRATION NUMBER: CRD420251001413.

Authors with CRIS profile

Involved external institutions

University of Oslo Norway (NO) Aarhus University Hospital / Aarhus Universitetshospital Denmark (DK) Steno Diabetes Center Denmark (DK) Aarhus University Denmark (DK) Vrije Universiteit Amsterdam (VU) / University Amsterdam Netherlands (NL) Medizinische Universität Wien Austria (AT) University of Ioannina / Πανεπιστήμιο Ιωαννίνων Greece (GR) Gentofte Hospital Denmark (DK) Odense Universitetshospital (OUH) Denmark (DK) Rigshospitalet Denmark (DK) Mario Negri Institute for Pharmacological Research (IRCCS) / Istituto di Ricerche Farmacologiche Mario Negri Italy (IT) University Health Network (UHN) Canada (CA) UT Health San Antonio United States (USA) (US) Regionshospitalet Gødstrup Denmark (DK) Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra Netherlands (NL) University Medical Center Groningen (UMCG) / Universitair Medisch Centrum Groningen Netherlands (NL) University Medical Centre Utrecht (UMC Utrecht) Netherlands (NL) University of British Columbia Canada (CA)

How to cite

APA:

Kugathasan, L., Nardone, M., Muskiet, M.H., Diaz Martinez, J.P., Lovblom, L.E., Orchanian-Cheff, A.,... Srinivasan Sridhar, V. (2026). Mechanisms of SGLT inhibitor action and physiological mediators: systematic review and protocol for the MOSAIC collaborative meta-analysis. BMJ Open, 16(2), e108946-. https://doi.org/10.1136/bmjopen-2025-108946

MLA:

Kugathasan, Luxcia, et al. "Mechanisms of SGLT inhibitor action and physiological mediators: systematic review and protocol for the MOSAIC collaborative meta-analysis." BMJ Open 16.2 (2026): e108946-.

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