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How can this protect the kidneys and heart from failing as observed in individuals with and without type 2 diabetes?<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>GOAL<\/jats:title>\n                    <jats:p>Mediation analyses identified clinical phenotypes of SGLT2i associated with improved kidney and heart outcome, including a reduction of plasma volume or increase in hematocrit, and lowering of serum urate levels and albuminuria. This review outlines how primary effects of SGLT2i on the early proximal tubule can explain these phenotypes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>The physiology of tubule-glomerular communication provides the basis for acute lowering of GFR and glomerular capillary pressure, which contributes to lowering of albuminuria but also to long term preservation of GFR, at least in part by reducing kidney cortex oxygen demand. Functional co-regulation of SGLT2 with other sodium and metabolite transporters in the early proximal tubule explains why SGLT2i initially excrete more sodium than expected and are uricosuric, thereby reducing plasma volume and serum urate. Inhibition of SGLT2 reduces early proximal tubule gluco-toxicity and by shifting transport downstream may simulate \u201csystemic hypoxia\u201d, and the resulting increase in erythropoiesis, together with the osmotic diuresis, enhances hematocrit and improves blood oxygen delivery. Cardio-renal protection by SGLT2i is also provided by a fasting-like and insulin-sparing metabolic phenotype and, potentially, by off-target effects on the heart and microbiotic formation of uremic toxins.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/ajh\/hpae092","type":"journal-article","created":{"date-parts":[[2024,7,17]],"date-time":"2024-07-17T11:33:11Z","timestamp":1721215991000},"page":"841-852","source":"Crossref","is-referenced-by-count":114,"title":["State-of-the-Art-Review: Mechanisms of Action of SGLT2 Inhibitors and Clinical Implications"],"prefix":"10.1093","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9211-2063","authenticated-orcid":false,"given":"Volker","family":"Vallon","sequence":"first","affiliation":[{"name":"Division of Nephrology and Hypertension, Department of Medicine, University of California San Diego , La Jolla, California ,","place":["USA"]},{"name":"Department of Pharmacology, University of California San Diego , La Jolla, California ,","place":["USA"]},{"name":"VA San Diego Healthcare System , San Diego, California ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,7,17]]},"reference":[{"key":"2025071620012899300_CIT0001","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1007\/s00424-020-02361-w","article-title":"Glucose transporters in the kidney in health and disease","volume":"472","author":"Vallon","year":"2020","journal-title":"Pflugers Arch"},{"key":"2025071620012899300_CIT0002","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1016\/S0140-6736(22)02074-8","article-title":"Impact of diabetes on the effects of sodium glucose co-transporter-2 inhibitors on kidney outcomes: collaborative meta-analysis of large placebo-controlled trials","volume":"400","author":"Nuffield Department of Population Health Renal Studies Group, Consortium SiM-AC-RT","year":"2022","journal-title":"Lancet"},{"key":"2025071620012899300_CIT0003","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/S2213-8587(21)00242-4","article-title":"Effect of dapagliflozin on the rate of decline in kidney function in patients with chronic kidney disease with and without type 2 diabetes: a prespecified analysis from the DAPA-CKD trial","volume":"9","author":"Heerspink","year":"2021","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2025071620012899300_CIT0004","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1016\/S0140-6736(22)01429-5","article-title":"SGLT-2 inhibitors in patients with heart failure: a comprehensive meta-analysis of five randomised controlled trials","volume":"400","author":"Vaduganathan","year":"2022","journal-title":"Lancet"},{"key":"2025071620012899300_CIT0005","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1681\/ASN.2010030246","article-title":"SGLT2 mediates glucose reabsorption in the early proximal tubule","volume":"22","author":"Vallon","year":"2011","journal-title":"J Am Soc Nephrol"},{"key":"2025071620012899300_CIT0006","doi-asserted-by":"crossref","first-page":"187","DOI":"10.2337\/db11-1029","article-title":"Na(+)-d-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion","volume":"61","author":"Gorboulev","year":"2012","journal-title":"Diabetes"},{"key":"2025071620012899300_CIT0007","doi-asserted-by":"crossref","first-page":"F188","DOI":"10.1152\/ajprenal.00518.2013","article-title":"Increase in SGLT1-mediated transport explains renal glucose reabsorption during genetic and pharmacological SGLT2 inhibition in euglycemia","volume":"306","author":"Rieg","year":"2014","journal-title":"Am J Physiol Renal Physiol"},{"key":"2025071620012899300_CIT0008","doi-asserted-by":"crossref","first-page":"356","DOI":"10.2337\/dc17-1096","article-title":"How does empagliflozin reduce cardiovascular mortality? 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