TY - JOUR
T1 - Mechanisms of SGLT inhibitor action and physiological mediators
T2 - systematic review and protocol for the MOSAIC collaborative meta-analysis
AU - Kugathasan, Luxcia
AU - Nardone, Massimo
AU - Muskiet, Marcel Ha
AU - Diaz Martinez, Juan Pablo
AU - Lovblom, Leif Erik
AU - Orchanian-Cheff, Ani
AU - Nielsen, Steffen
AU - Rotbain, Viktor
AU - Kazup, Agota
AU - Cersosimo, Eugenio
AU - Gullaksen, Soren
AU - Vernstrom, Liv
AU - van Baar, Michael J B
AU - van Bommel, Erik
AU - Kannenkeril, Dennis
AU - Scholtes, Rosalie
AU - Hesp, Anne
AU - Mosterd, Charlotte
AU - Touw, Daan J
AU - Lambers Heerspink, Hiddo
AU - Krebber, Merle
AU - Joles, Jaap
AU - Kvitne, Kine
AU - Laugesen, Esben
AU - Mose, Frank
AU - Mårup, Frederik Husum
AU - Nieuwdorp, Max
AU - Geist, Barbara
AU - Maruyama, Shoichi
AU - Kato, Sawako
AU - Kalambokis, Georgios
AU - Tsiakas, Ilias
AU - Jensen, Jesper
AU - Schou, Morten
AU - Omar, Massar
AU - Kistorp, Caroline Michaela
AU - Perna, Annalisa
AU - Ruggenenti, Piero
AU - Persson, Frederik
AU - Schmieder, Roland
AU - Singh, Sunita
AU - van Raalte, Daniel H
AU - Cherney, David
AU - Srinivasan Sridhar, Vikas
N1 - Publisher Copyright:
© Author(s) (or their employer(s)) 2026. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group.. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: https://creativecommons.org/licenses/by-nc/4.0/.
PY - 2026/2/25
Y1 - 2026/2/25
N2 - 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.
AB - 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.
KW - Glomerular Filtration Rate/drug effects
KW - Hemodynamics/drug effects
KW - Humans
KW - Kidney/drug effects
KW - Meta-Analysis as Topic
KW - Research Design
KW - Sodium-Glucose Transporter 2 Inhibitors/pharmacology
KW - Systematic Reviews as Topic
U2 - 10.1136/bmjopen-2025-108946
DO - 10.1136/bmjopen-2025-108946
M3 - Article
C2 - 41748173
SN - 2044-6055
VL - 16
JO - BMJ Open
JF - BMJ Open
IS - 2
M1 - e108946
ER -