Metabolic Communication by SGLT2 Inhibition.

Background: SGLT2 (sodium-glucose cotransporter 2) inhibitors (SGLT2i) can protect the kidneys and heart, but the underlying mechanism remains poorly understood.
Methods: To gain insights on primary effects of SGLT2i that are not confounded by pathophysiologic processes or are secondary to improvement by SGLT2i, we performed an in-depth proteomics, phosphoproteomics, and metabolomics analysis by integrating signatures from multiple metabolic organs and body fluids after 1 week of SGLT2i treatment of nondiabetic as well as diabetic mice with early and uncomplicated hyperglycemia.
Results: Kidneys of nondiabetic mice reacted most strongly to SGLT2i in terms of proteomic reconfiguration, including evidence for less early proximal tubule glucotoxicity and a broad downregulation of the apical uptake transport machinery (including sodium, glucose, urate, purine bases, and amino acids), supported by mouse and human SGLT2 interactome studies. SGLT2i affected heart and liver signaling, but more reactive organs included the white adipose tissue, showing more lipolysis, and, particularly, the gut microbiome, with a lower relative abundance of bacteria taxa capable of fermenting phenylalanine and tryptophan to cardiovascular uremic toxins, resulting in lower plasma levels of these compounds (including p-cresol sulfate). SGLT2i was detectable in murine stool samples and its addition to human stool microbiota fermentation recapitulated some murine microbiome findings, suggesting direct inhibition of fermentation of aromatic amino acids and tryptophan. In mice lacking SGLT2 and in patients with decompensated heart failure or diabetes, the SGLT2i likewise reduced circulating p-cresol sulfate, and p-cresol impaired contractility and rhythm in human induced pluripotent stem cell-derived engineered heart tissue.
Conclusions: SGLT2i reduced microbiome formation of uremic toxins such as p-cresol sulfate and thereby their body exposure and need for renal detoxification, which, combined with direct kidney effects of SGLT2i, including less proximal tubule glucotoxicity and a broad downregulation of apical transporters (including sodium, amino acid, and urate uptake), provides a metabolic foundation for kidney and cardiovascular protection.
Competing Interests: Disclosures Dr Rinschen declares pending research funding from Novo Nordisk unrelated to this work. Over the past 12 months, Dr Vallon has served as a consultant for Lexicon and received speaker honoraria from AstraZeneca and grant support for investigator-initiated research from AstraZeneca, Boehringer Ingelheim, Gilead, Lexicon, Maze, Merck, and Novo-Nordisk. Dr Magnussen receives study-specific funding from the German Center for Cardiovascular Research (DZHK; Promotion of Women Scientists Programme; FKZ 81X3710112), the Deutsche Stiftung für Herzforschung, the Dr Rolf M. Schwiete Stiftung, NDD, and Loewenstein Medical unrelated to the current work. Dr Magnussen has received speaker fees from AstraZeneca, Novartis, Boehringer Ingelheim/Lilly, Bayer, Pfizer, Sanofi, Aventis, Apontis, and Abbott outside this work. Dr Dugourd and R. Fallegger report funding from Pfizer. Dr Saez-Rodriguez reports funding from GSK, Pfizer, and Sanofi and fees from Travere Therapeutics, Stadapharm, and Astex. Dr Hoxha served on advisory boards for Novartis, Morphosys AG, Sotio, and Argenx. The other authors declare no conflict of interest.