{
  "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": [
    {
      "affiliations": [
        "University Health Network, Toronto, Ontario, Canada",
        "University of Toronto Faculty of Medicine, Toronto, Ontario, Canada"
      ],
      "name": "Luxcia Kugathasan"
    },
    {
      "affiliations": [
        "University Health Network, Toronto, Ontario, Canada"
      ],
      "name": "Massimo Nardone"
    },
    {
      "affiliations": [
        "University Health Network, Toronto, Ontario, Canada",
        "Department of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, Netherlands"
      ],
      "name": "Marcel HA Muskiet"
    },
    {
      "affiliations": [
        "Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada"
      ],
      "name": "Juan Pablo Diaz Martinez"
    },
    {
      "affiliations": [
        "Biostatistics Research Unit, University Health Network, Toronto, Ontario, Canada",
        "University of Toronto Institute of Health Policy Management and Evaluation, Toronto, Ontario, Canada"
      ],
      "name": "Leif Erik Lovblom"
    },
    {
      "affiliations": [
        "Library and Information Services, University Health Network, Toronto, Ontario, Canada"
      ],
      "name": "Ani Orchanian-Cheff"
    },
    {
      "affiliations": [
        "Gødstrup Hospital, Herning, Central Denmark Region, Denmark"
      ],
      "name": "Steffen Nielsen"
    },
    {
      "affiliations": [
        "Steno Diabetes Center Copenhagen, Herlev, Capital Region of Denmark, Denmark"
      ],
      "name": "Viktor Rotbain"
    },
    {
      "affiliations": [
        "Steno Diabetes Center Copenhagen, Herlev, Capital Region of Denmark, Denmark"
      ],
      "name": "Agota Kazup"
    },
    {
      "affiliations": [
        "Medicine, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA",
        "University Health Texas Diabetes Institute, San Antonio, Texas, USA"
      ],
      "name": "Eugenio Cersosimo"
    },
    {
      "affiliations": [
        "Aarhus University, Aarhus, Denmark"
      ],
      "name": "Soren Gullaksen"
    },
    {
      "affiliations": [
        "Aarhus University, Aarhus, Denmark"
      ],
      "name": "Liv Vernstrom"
    },
    {
      "affiliations": [
        "Diabetes Center, Department of Internal Medicine, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Michael J B van Baar"
    },
    {
      "affiliations": [
        "Diabetes Center, Department of Internal Medicine, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands",
        "Radboud University Medical Center, Nijmegen, The Netherlands"
      ],
      "name": "Erik van Bommel"
    },
    {
      "affiliations": [
        "Erlangen University Hospital Department of Medicine 4 Nephrology and Hypertension, Erlangen, BY, Germany"
      ],
      "name": "Dennis Kannenkeril"
    },
    {
      "affiliations": [
        "Diabetes Center, Department of Internal Medicine, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Rosalie Scholtes"
    },
    {
      "affiliations": [
        "Diabetes Center, Department of Internal Medicine, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Anne Hesp"
    },
    {
      "affiliations": [
        "Diabetes Center, Department of Internal Medicine, VU University Medical Centre Amsterdam, Amsterdam, The Netherlands"
      ],
      "name": "Charlotte Mosterd"
    },
    {
      "affiliations": [
        "Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Daan J Touw"
    },
    {
      "affiliations": [
        "University Medical Center Groningen, Groningen, The Netherlands"
      ],
      "name": "Hiddo Lambers Heerspink"
    },
    {
      "affiliations": [
        "Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, The Netherlands"
      ],
      "name": "Merle Krebbe"
    },
    {
      "affiliations": [
        "Department of Nephrology and Hypertension, University Medical Centre Utrecht, Utrecht, The Netherlands"
      ],
      "name": "Jaap Joles"
    },
    {
      "affiliations": [
        "Department of Pharmacy, University of Oslo, Oslo, Norway"
      ],
      "name": "Kine Kvitne"
    },
    {
      "affiliations": [
        "Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark"
      ],
      "name": "Esben Laugesen"
    },
    {
      "affiliations": [
        "Steno Diabetes Center Copenhagen, Herlev, Capital Region of Denmark, Denmark",
        "Aarhus University Hospital, Aarhus, Central Denmark Region, Denmark"
      ],
      "name": "Frank Mose"
    },
    {
      "affiliations": [
        "Dept. of Biomedicine, Aarhus University, Aarhus, Denmark",
        "Dept. of Renal Medicine, Aarhus University Hospital, Aarhus, Denmark"
      ],
      "name": "Frederik Husum Mårup"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Amsterdam UMC, Vrije Universiteit Amsterdam, Academisch Medisch Centrum, Amsterdam, The Netherlands"
      ],
      "name": "Max Nieuwdorp"
    },
    {
      "affiliations": [
        "Medical University of Vienna, Vienna, Austria"
      ],
      "name": "Barbara Geist"
    },
    {
      "affiliations": [
        "Department of Nephrology, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Japan"
      ],
      "name": "Shoichi Maruyama"
    },
    {
      "affiliations": [
        "Department of Nephrology, Nagoya Daigaku Daigakuin Igakukei Kenkyuka Igakubu, Nagoya, Japan"
      ],
      "name": "Sawako Kato"
    },
    {
      "affiliations": [
        "First Division of Internal Medicine, University of Ioannina, Ioannina, Ipiros Ditiki Makedonia, Greece"
      ],
      "name": "Georgios Kalambokis"
    },
    {
      "affiliations": [
        "First Division of Internal Medicine, University of Ioannina, Ioannina, Ipiros Ditiki Makedonia, Greece"
      ],
      "name": "Ilias Tsiakas"
    },
    {
      "affiliations": [
        "Department of Cardiology, Herlev and Gentofte University Hospital, Copenhagen, Denmark"
      ],
      "name": "Jesper Jensen"
    },
    {
      "affiliations": [
        "Cardiology, Herlev Hospital, Herlev, Denmark"
      ],
      "name": "Morten Schou"
    },
    {
      "affiliations": [
        "Department of Cardiology, Odense University Hospital Department of Cardiology B, Odense C, Region Syddanmark, Denmark"
      ],
      "name": "Massar Omar"
    },
    {
      "affiliations": [
        "Department of Endocrinology, Rigshospitalet, Copenhagen, Denmark"
      ],
      "name": "Caroline Michaela Kistorp"
    },
    {
      "affiliations": [
        "Mario Negri Institute for Pharmacological Research, Bergamo, Italy"
      ],
      "name": "Annalisa Perna"
    },
    {
      "affiliations": [
        "Mario Negri Institute for Pharmacological Research, Bergamo, Italy",
        "Unit of Nephrology and Dialysis, Azienda Socio Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy"
      ],
      "name": "Piero Ruggenenti"
    },
    {
      "affiliations": [
        "Steno Diabetes Center Copenhagen, Gentofte, Denmark"
      ],
      "name": "Frederik Persson"
    },
    {
      "affiliations": [
        "Department of Nephrology and Hypertension, University Hospital Erlangen, Erlangen, Germany"
      ],
      "name": "Roland Schmieder"
    },
    {
      "affiliations": [
        "Ajmera Transplant Centre and the Division of Nephrology, University Health Network, Toronto, Ontario, Canada"
      ],
      "name": "Sunita Singh"
    },
    {
      "affiliations": [
        "Department of Endocrinology, Amsterdam University Medical Center, Amsterdam, The Netherlands",
        "Amsterdam Cardiovascular Sciences Research Institute, Amsterdam, The Netherlands"
      ],
      "name": "Daniel H van Raalte"
    },
    {
      "affiliations": [
        "University Health Network, Toronto, Ontario, Canada"
      ],
      "name": "David Cherney"
    },
    {
      "affiliations": [
        "Division of Nephrology, The University of British Columbia Faculty of Medicine, Vancouver, British Columbia, Canada"
      ],
      "name": "Vikas Srinivasan Sridhar"
    }
  ],
  "title": "Mechanisms of SGLT inhibitor action and physiological mediators: systematic review and protocol for the MOSAIC collaborative meta-analysis",
  "uid": "8b5c325d-a94e-57b3-ac37-60253c9d8307"
}