Mechanisms of heart failure and chronic kidney disease protection by SGLT2 inhibitors in nondiabetic conditions
Abstract
Sodium-glucose cotransporter 2 inhibitors (SGLT2is), initially developed for type 2 diabetes (T2D) treatment, have demonstrated significant cardiovascular and renal benefits in heart failure (HF) and chronic kidney disease (CKD), irrespective of T2D. This review provides an analysis of the multifaceted mechanisms underlying the cardiorenal benefits of SGLT2i in HF and CKD outside of the T2D context. Eight major aspects of the protective effects of SGLT2i beyond glycemic control are explored: 1 ) the impact on renal hemodynamics and tubuloglomerular feedback; 2 ) the natriuretic effects via proximal tubule Na + /H + exchanger NHE3 inhibition; 3 ) the modulation of neurohumoral pathways with evidence of attenuated sympathetic activity; 4 ) the impact on erythropoiesis, not only in the context of local hypoxia but also systemic inflammation and iron regulation; 5 ) the uricosuria and mitigation of the hyperuricemic environment in cardiorenal syndromes; 6 ) the multiorgan metabolic reprogramming including the potential induction of a fasting-like state, improvement in glucose and insulin tolerance, and stimulation of lipolysis and ketogenesis; 7 ) the vascular endothelial growth factor A (VEGF-A) upregulation and angiogenesis, and 8 ) the direct cardiac effects. The intricate interplay between renal, neurohumoral, metabolic, and cardiac effects underscores the complexity of SGLT2i actions and provides valuable insights into their therapeutic implications for HF and CKD. Furthermo…
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Recent data support that SGLT2 inhibitors reduce oxidative stress in the kidney by >50% and blunt increases in angiotensinogen as well as reduce NLRP3 inflammasome activity.
“Moreover, recent data support the notion that SGLT2 inhibitors reduce oxidative stress in the kidney by >50% and blunt increases in angiotensinogen as well as reduce NLRP3 inflammasome activity (100,102,103).”
From 11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026 (2026) · cites this paper as [100]
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11. Chronic Kidney Disease and Risk Management: Standards of Care in Diabetes—2026
American Diabetes Association Professional Practice Committee for Diabetes*, Bajaj, M., McCoy, R. G., Balapattabi, K., Bannuru, R. R., Bellini, N. J., Bennett, A. K., Beverly, E. A., Briggs Early, K., ChallaSivaKanaka, S., et al. (2026) · Diabetes Care · doi:10.2337/dc26-s011 · Cited by 108 · see citing works
- Authors
- Girardi, A. C. C., Polidoro, J. Z., Castro, P. C., Pio-Abreu, A., Noronha, I. L., & Drager, L. F.
- Affiliations
- Universidade de São Paulo (BR)
- Laboratório de Genética e Cardiologia Molecular, Faculdade de Medicina, Instituto do Coração (InCor), Hospital das Clínicas HCFMUSP, Universidade de São Paulo, São Paulo, Brazil
- Corresponding author
- Girardi, Adriana C. C.
- Polidoro, Juliano Z.
- ORCID
- Venue
- American Journal of Physiology-Cell Physiology
- Publisher
- American Physiological Society
- Published
- 2024-09-01
- Volume
- 327
- Issue
- 3
- Pages
- C525-C544
- ISSN
- 0363-6143 (ISSN-L)
- 1522-1563
- OpenAlex
- W4399725765
- Cited by
- 32
- References
- 14
- Citations by year
- 2026: 18 · 2025: 13 · 2024: 1
- FWCI
- 1.88
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Cell Physiology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Fundação de Amparo à Pesquisa do Estado de São Paulo (2021/14534-3, 2019/23496-8, 2020/05668-2)
- Conselho Nacional de Desenvolvimento Científico e Tecnológico (304666/2022-0, 2022/310717)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
- Keywords
- SGLT2 inhibitors, heart failure, chronic kidney disease, cardiorenal protection, non-diabetic patients, renal hemodynamics, tubuloglomerular feedback, NHE3 inhibition, sodium excretion, sympathetic nervous system, erythropoiesis, hypoxia, systemic inflammation, iron regulation, uricosuria, hyperuricemia, cardiorenal syndrome, metabolic reprogramming, insulin tolerance, lipolysis, ketogenesis, VEGF-A, angiogenesis, endothelial function, cardiac effects
- MeSH terms
- Sodium-Hydrogen Exchanger 3, Sodium-Glucose Transporter 2 Inhibitors, Animals, Heart Failure, Humans, Kidney, Renal Insufficiency, Chronic
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