ArticleThe Journal of clinical investigation2024
SGLT2 inhibition alters substrate utilization and mitochondrial redox in healthy and failing rat hearts.
Article in The Journal of clinical investigation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed.
- Metabolic and redox pathway dysregulation in HIV-associated coronary endothelial dysfunction.American journal of physiology. Heart and circulatory physiology · 2026Observational
- Apabetalone Drives a Metabolic Shift Towards Ketogenesis and Reduces Liver Steatosis in Diet-Induced Obesity Mice.Biomedicines · 2026Article
- Decoding cardiorenal crosstalk: Intercellular communication mechanisms and therapeutic insights in cardiorenal syndrome.iScience · 2026Review
- Randomized Controlled Trial of Dapagliflozin for Post-Transplant Diabetes Mellitus in Renal Transplant Recipients.Kidney international reports · 2026Article
- Electrostatic lipidopathy drives human diabetic heart failure.Cardiovascular diabetology. Endocrinology reports · 2026Article
- Target trial emulation of sodium glucose cotransporter 2 inhibitors and clinical outcomes in diabetes and end stage kidney disease.Scientific reports · 2026Article
- Sodium-glucose Co-transporter 2 (SGLT2) inhibitor dapagliflozin acutely activates cardiomyocyte HIF-1α signaling via succinate, a signaling metabolite.Journal of pharmacological sciences · 2026Article
- Mechanisms and Therapeutic Potential of Sodium-Glucose Cotransporter 2 Inhibitors in Heart Failure.Reviews in cardiovascular medicine · 2026Review
- Mechanistic Links Between the Gut Microbiome and Longevity Therapeutics.Biomedicines · 2026Review
- Diabetes and cancer: therapeutic implications.Cardio-oncology (London, England) · 2026Review
- Research Progress of SGLT2 Inhibitors in the Treatment of Acute Heart Failure: A Narrative Review.International journal of general medicine · 2026Review
- Modulation of oxidative stress and metabolic burden in papillary thyroid cancer by SGLT2 and broad DPP inhibition.Frontiers in molecular biosciences · 2026Article
- Current understanding of sodium-glucose transporter 2 inhibitors in cardiovascular-kidney-metabolic syndrome.Frontiers in pharmacology · 2026Review
- Direct dapagliflozin exposure enhances respiration and membrane hyperpolarization in isolated cardiac mitochondria.Frontiers in physiology · 2026Article
- SGLT2 inhibitors prevent long-COVID-associated cognitive and pain symptoms in type 2 diabetes patients.Virology journal · 2025Article
- Dapagliflozin alleviates sunitinib-induced cardiotoxicity through AMPKα-PPARα axis and enhances the sensitivity of renal cell carcinoma to sunitinib.BMC medicine · 2025Article
- SGLT2 inhibitors in cardiac amyloidosis: mechanistic insights and clinical perspectives-a narrative review.Cardiovascular diabetology. Endocrinology reports · 2025Review
- Cardiac intermediary metabolism in heart failure: substrate use, signalling roles and therapeutic targets.Nature reviews. Cardiology · 2025Review
- Sodium-glucose cotransporter 2 inhibitors alleviate renal fibrosis in diabetic kidney disease by inhibiting Hmgcs2 and Btg2 in proximal tubular cells.Journal of translational medicine · 2025Article
- SGLT2 Inhibitors: Multifaceted Therapeutic Agents in Cardiometabolic and Renal Diseases.Metabolites · 2025Review
Corrections and comments
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Authors and funding
23 authors.
Funding
Abstract
Previous studies highlight the potential for sodium-glucose cotransporter type 2 (SGLT2) inhibitors (SGLT2i) to exert cardioprotective effects in heart failure by increasing plasma ketones and shifting myocardial fuel utilization toward ketone oxidation. However, SGLT2i have multiple in vivo effects and the differential impact of SGLT2i treatment and ketone supplementation on cardiac metabolism remains unclear. Here, using gas chromatography-mass spectrometry (GC-MS) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methodology combined with infusions of [13C6]glucose or [13C4]βOHB, we demonstrate that acute SGLT2 inhibition with dapagliflozin shifts relative rates of myocardial mitochondrial metabolism toward ketone oxidation, decreasing pyruvate oxidation with little effect on fatty acid oxidation in awake rats. Shifts in myocardial ketone oxidation persisted when plasma glucose levels were maintained. In contrast, acute βOHB infusion similarly augmented ketone oxidation, but markedly reduced fatty acid oxidation and did not alter glucose uptake or pyruvate oxidation. After inducing heart failure, dapagliflozin increased relative rates of ketone and fatty acid oxidation, but decreased pyruvate oxidation. Dapagliflozin increased mitochondrial redox and reduced myocardial oxidative stress in heart failure, which was associated with improvements in left ventricular ejection fraction after 3 weeks of treatment. Thus, SGLT2i have pleiotropic effects on systemic and heart metabolism, which are distinct from ketone supplementation and may contribute to the long-term cardioprotective benefits of SGLT2i.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.