Metabolic Communication by SGLT2 Inhibition

Abstract

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–engineered heart tissue. CONCLUSION: 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.

Indoxyl Sulfate-Induced Macrophage Toxicity and Therapeutic Strategies in Uremic Atherosclerosis

“…Canagliflozin, a SGLT2 inhibitor, optimized gut microbiota composition via increased cecal short-chain fatty acids, reduced serum IS levels, and suppressed systemic inflammation and kidney injury [ 120 ]. SGLT2 inhibitors have also been shown to alter the gut microbiota and potentially reduce the production of uremic toxins derived from amino acids, as revealed in proteomics analyses using mice [ 121 ].…”

Blood-based cardiometabolic phenotypes in atrial fibrillation and their associated risk: EAST-AFNET 4 biomolecule study

“… 3 , 4 More than 80% of patients with AF suffer from comorbidities, such as hypertension, heart failure, diabetes, or coronary, cerebral, or peripheral artery disease at the time of diagnosing AF. 4 , 5 These include cardiometabolic dysfunction, 6 systemic and atrial thromboinflammation, 7 , 8 vascular and endothelial dysfunction, 7 , 8 and cardiomyocyte dysfunction. 9 Quantification of underlying disease processes and their interactions may identify drivers of cardiovascular complications in patients with AF.…”

Dapagliflozin and atrial fibrillation: elevated dosing to achieve class I antiarrhythmic effects?

“…Empagliflozin also ameliorated anthracycline-associated cardiotoxicity [ 15 ] leading to the multicenter phase 3 study EMPACT (NCT05271162). Finally, a recent unbiased proteomics and metabolomics study showed that SGLT2i mainly affect the gut microbiome and the kidney, where they induce less production and greater excretion of amino acid metabolites (“uremic toxins”) with cardiodepressant effects [ 2 ].…”