SGLT2 inhibitor: 2-way superstar in nephrology?

Shohei Ohtani became an amazing 2-way player in a modern-day game of baseball that basically never sees them, and he won his second American League most valuable player award unanimously in 2023. Perhaps we can consider sodium-glucose cotransporter 2 (SGLT2) inhibitors as a 2-way player and most valuable player in the effort to slow the progression of kidney disease. SGLT2 inhibitors showed big success in many clinical trials. Because kidney protection by SGLT2 inhibitors is so consistent and powerful, investigators are going back to preclinical studies to reveal the mechanisms of kidney protection by SGLT2 inhibitors. We now realize that SGLT2 inhibitor may be a 2-way reagent that protects the kidney via 2 important mechanisms: one is mediated by hemodynamic changes, whereas another is independent of hemodynamic effects. In this issue of Kidney International, 2 articles clearly summarized these mechanisms.1Yau K. Cherney D.Z.I. van Raalte D.H. Wever B.E. Kidney protective mechanisms of SGLT2 inhibitors: evidence for a hemodynamic effect.Kidney Int. 2024; 105: 1168-1172Google Scholar,2Kume S. Packer M. SGLT2 inhibitors act as metabolic transducers to restore healthy nutrient deprivation and surplus signaling in the kidney.Kidney Int. 2024; 105: 1172-1176Google Scholar Although SGLT2 inhibitors were originally developed as glucose-lowering agents, clinical studies repeatedly confirmed kidney protection by SGLT2 inhibitors. Analysis to compare kidney outcomes of patients who were newly treated with individual SGLT2 inhibitors using a large-scale real-world data set confirmed equivalent kidney outcomes between individual SGLT2 inhibitors, demonstrating that the kidney protection by SGLT2 inhibitors is the class-specific effect.3Suzuki Y. Kaneko H. Okada A. et al.Kidney outcomes in patients with diabetes mellitus did not differ between individual sodium-glucose cotransporter-2 inhibitors.Kidney Int. 2022; 102: 1147-1153Abstract Full Text Full Text PDF Scopus (12) Google Scholar SGLT2 inhibitors protected the kidney not only in patients with diabetic kidney disease but also in patients with nondiabetic kidney disease. Initiation of SGLT2 inhibitors induces an initial decrease in estimated glomerular filtration rate, which is similar to that observed in patients treated with renin-angiotensin inhibitors.4Nagasu H. Yano Y. Kanegae H. et al.Kidney outcomes associated with SGLT2 inhibitors versus other glucose-lowering drugs in real-world clinical practice: the Japan Chronic Kidney Disease Database.Diabetes Care. 2021; 44: 2542-2551Crossref PubMed Scopus (42) Google Scholar This initial decrease is reversible and eventually protects the kidney in the long-term. The mechanism of this decrease is considered to be due to amelioration of glomerular hyperfiltration via tubuloglomerular feedback.5van Bommel E.J.M. Muskiet M.H.A. van Baar M.J.B. et al.The renal hemodynamic effects of the SGLT2 inhibitor dapagliflozin are caused by post-glomerular vasodilatation rather than pre-glomerular vasoconstriction in metformin-treated patients with type 2 diabetes in the randomized, double-blind RED trial.Kidney Int. 2020; 97: 202-212Abstract Full Text Full Text PDF PubMed Scopus (221) Google Scholar Yau et al. comprehensively summarized this aspect in this issue.1Yau K. Cherney D.Z.I. van Raalte D.H. Wever B.E. Kidney protective mechanisms of SGLT2 inhibitors: evidence for a hemodynamic effect.Kidney Int. 2024; 105: 1168-1172Google Scholar However, the clinical benefit of SGLT2 inhibitors was observed regardless of the initial decrease,6Oshima M. Jardine M.J. Agarwal R. et al.Insights from CREDENCE trial indicate an acute drop in estimated glomerular filtration rate during treatment with canagliflozin with implications for clinical practice.Kidney Int. 2021; 99: 999-1009Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar and SGLT2 inhibitors may also protect the kidney via a mechanism beyond hemodynamic effects. Single-cell RNA-sequencing analysis using kidney biopsy tissue showed that treatment with SGLT2 inhibitors increased kidney tissue expression of epidermal growth factor and was associated with a downstream signaling cascade linked to tubular repair.7Sen T. Ju W. Nair V. et al.Sodium glucose co-transporter 2 inhibition increases epidermal growth factor expression and improves outcomes in patients with type 2 diabetes.Kidney Int. 2023; 104: 828-839Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar Studies using diabetic animals showed that SGLT2 inhibitors improve mitochondrial dysfunction and ameliorate oxidative stress.8Tanaka S. Sugiura Y. Saito H. et al.Sodium-glucose cotransporter 2 inhibition normalizes glucose metabolism and suppresses oxidative stress in the kidneys of diabetic mice.Kidney Int. 2018; 94: 912-925Abstract Full Text Full Text PDF PubMed Scopus (118) Google Scholar Analysis of the response of a murine diabetic kidney disease model using single-cell RNA sequencing showed that SGLT2 inhibitors induce hypoxia responses and fasting mimicry in the S1 segment of the proximal tubule, suggesting that the hypoxia pathway and the nutrient pathway play a central role in kidney protection by SGLT2 inhibitors.9Wu H. Gonzalez Villalobos R. Yao X. et al.Mapping the single-cell transcriptomic response of murine diabetic kidney disease to therapies.Cell Metab. 2022; 34: 1064-1078.e6Abstract Full Text Full Text PDF PubMed Scopus (67) Google Scholar Hypoxia is a final common pathway to end-stage kidney disease.10Nangaku M. Chronic hypoxia and tubulointerstitial injury: a final common pathway to end-stage renal failure.J Am Soc Nephrol. 2006; 17: 17-25Crossref PubMed Scopus (958) Google Scholar SGLT2 inhibitors improve anemia in chronic kidney disease and decrease oxygen demand in the kidney, thus improving a mismatch between oxygen delivery and oxygen demand of the kidney.11Hesp A.C. Schaub J.A. Prasad P.V. et al.The role of renal hypoxia in the pathogenesis of diabetic kidney disease: a promising target for newer renoprotective agents including SGLT2 inhibitors?.Kidney Int. 2020; 98: 579-589Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar To support this, post hoc analysis of the Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes trial (EMPA-REG OUTCOME) showed that changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits.12Wanner C. Nangaku M. Kraus B.J. et al.How do SGLT2 inhibitors protect the kidney? a mediation analysis of the EMPA-REG OUTCOME trial.Nephrol Dial Transplant. 2024; (Published online February 6, 2024)https://doi.org/10.1093/ndt/gfae032Crossref Google Scholar The nutrient pathway is also important, and Kume and Packer beautifully covered this aspect in this issue.2Kume S. Packer M. SGLT2 inhibitors act as metabolic transducers to restore healthy nutrient deprivation and surplus signaling in the kidney.Kidney Int. 2024; 105: 1172-1176Google Scholar SGLT2 inhibitors are beneficial in patients with heart failure, possibly due to an increase in ketone bodies and free fatty acids, which serve as an available energy fuel. Thus, SGLT2 inhibitors may act as modulators of nutrient deprivation and nutrient surplus signaling to restore homeostasis and metabolism of the kidney. The 2 articles1Yau K. Cherney D.Z.I. van Raalte D.H. Wever B.E. Kidney protective mechanisms of SGLT2 inhibitors: evidence for a hemodynamic effect.Kidney Int. 2024; 105: 1168-1172Google Scholar,2Kume S. Packer M. SGLT2 inhibitors act as metabolic transducers to restore healthy nutrient deprivation and surplus signaling in the kidney.Kidney Int. 2024; 105: 1172-1176Google Scholar give us deep insights about SGLT2 inhibitors and the pathophysiology of kidney disease. The author declared no competing interests. SGLT2 inhibitors act as metabolic transducers to restore healthy nutrient deprivation and surplus signaling in the kidneyKidney InternationalVol. 105Issue 6PreviewIn the healthy adult kidney, cellular homeostasis is maintained by the balance between nutrient surplus and nutrient deprivation signaling.1 The primary nutrient deprivation signals are sirtuin 1 (SIRT1) and adenosine monophosphate protein kinase (AMPK), which are activated by low intracellular levels of glucose and adenosine triphosphate (ATP) and by the oxidation-reduction state, and function to reduce oxidative stress and proinflammatory signaling, thus promoting cellular survival. The primary nutrient surplus signals are mammalian target of rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α), which are activated by high intracellular levels of glucose to enhance flux through glucose-driven anabolic pathways and to promote maladaptive tubular hypertrophy, oxidative stress, inflammation, fibrosis, and apoptosis. Full-Text PDF Kidney protective mechanisms of SGLT2 inhibitors: evidence for a hemodynamic effectKidney InternationalVol. 105Issue 6PreviewSodium-glucose cotransporter-2 (SGLT2) inhibitors were introduced a decade ago for the treatment of type 2 diabetes (T2D) and have emerged as a key therapy for the treatment of chronic kidney disease (CKD). In trials with primary kidney end points, SGLT2 inhibitors reduced the composite of kidney failure, kidney death, and doubling of serum creatinine by 28% to 39%.1 Benefits of this class of medication are independent of glycemic lowering, as glucose lowering with other drug classes has not been associated with similar improvements in kidney outcomes. Full-Text PDF