ArticleCardiovascular research2021
Off-target effects of sodium-glucose co-transporter 2 blockers: empagliflozin does not inhibit Na+/H+ exchanger-1 or lower [Na+]i in the heart.
Article in Cardiovascular research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 81 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Who cites it
81 citing papers in PubMed, 1 synthesis or guideline pooled it, 137 citations in OpenAlex.
- Effect of sodium-glucose cotransporter 2 inhibitors on cardiac structure and function in type 2 diabetes mellitus patients with or without chronic heart failure: a meta-analysis.Cardiovascular diabetology · 2021Pooled it
- Efficacy of empagliflozin as adjunctive therapy to citalopram in major depressive disorder: a randomized double-blind, placebo-controlled clinical trial.BMC psychiatry · 2024Trial
- Effect of dapagliflozin on ventricular arrhythmias, resuscitated cardiac arrest, or sudden death in DAPA-HF.European heart journal · 2021Trial
- Empagliflozin restores cardiac function in obese-diabetic HFpEF mice but further alters gene expression.Basic research in cardiology · 2026Article
- Cardioprotective properties of empagliflozin and other SGLT2 inhibitors.Nature reviews. Cardiology · 2026Review
- Cardiac SGLT2 Expression and Cell-Type-Specific Responses to Empagliflozin in iPSC-Derived Models of Diabetic Cardiomyopathy.Journal of cardiovascular development and disease · 2026Article
- Empagliflozin Attenuates Cardiac Dysfunction in Rat Model of Metabolic Syndrome: Evaluating Role of the Cardiac Renin-Angiotensin System.Biomedicines · 2026Article
- Sodium-glucose cotransporter 2 inhibitors in breast cancer patients on endocrine therapy: a targeted strategy to mitigate long-term cardiometabolic risk.Journal of translational medicine · 2026Review
- SGLT2 Inhibitors in Hypertrophic Cardiomyopathy: Emerging Evidence and Putative Mechanisms.Biomolecules · 2026Review
- Chronic kidney disease-associated cardiomyopathy: clinical features, pathophysiology and treatment.Nature reviews. Cardiology · 2026Review
- Review
- SGLT2 Inhibitors: From Molecular Mechanisms to Clinical Outcomes in Cardiology and Diabetology.Molecules (Basel, Switzerland) · 2025Review
- Cardiac digital twins: a tool to investigate the function and treatment of the diabetic heart.Cardiovascular diabetology · 2025Review
- Inflammasome Signaling in Cardiac Arrhythmias: Linking Inflammation, Fibrosis, and Electrical Remodeling.International journal of molecular sciences · 2025Review
- Differential sex-dependent susceptibility to diastolic dysfunction and arrhythmia in cardiomyocytes from obese diabetic heart failure with preserved ejection fraction model.Cardiovascular research · 2025Article
- Single cell transcriptomic analysis of SGLT2 expression supports an indirect or off-target role for the cardioprotective benefits of empagliflozin in heart failure.Scientific reports · 2025Article
- SGLT2 inhibitors: how do they affect the cardiac cells.Molecular and cellular biochemistry · 2025Review
- Sodium glucose transporter 2 inhibitors: Will these drugs benefit non-diabetic veterinary patients with cardiac and kidney diseases?Journal of veterinary pharmacology and therapeutics · 2025Review
- Roles of Empagliflozin in Diabetic Cardiomyopathy: A Review.Current vascular pharmacology · 2025Review
- Scientific criticism. A plea for continuous and open peer review.Frontiers in physiology · 2025Article
21 more citing papers are in PubMed but not listed here.
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
aimsEmipagliflozin (EMPA) is a potent inhibitor of the renal sodium-glucose co-transporter 2 (SGLT2) and an effective treatment for type-2 diabetes. In patients with diabetes and heart failure, EMPA has cardioprotective effects independent of improved glycaemic control, despite SGLT2 not being expressed in the heart. A number of non-canonical mechanisms have been proposed to explain these cardiac effects, most notably an inhibitory action on cardiac Na+/H+ exchanger 1 (NHE1), causing a reduction in intracellular [Na+] ([Na+]i). However, at resting intracellular pH (pHi), NHE1 activity is very low and its pharmacological inhibition is not expected to meaningfully alter steady-state [Na+]i. We re-evaluate this putative EMPA target by measuring cardiac NHE1 activity. METHODS AND
resultsThe effect of EMPA on NHE1 activity was tested in isolated rat ventricular cardiomyocytes from measurements of pHi recovery following an ammonium pre-pulse manoeuvre, using cSNARF1 fluorescence imaging. Whereas 10 µM cariporide produced near-complete inhibition, there was no evidence for NHE1 inhibition with EMPA treatment (1, 3, 10, or 30 µM). Intracellular acidification by acetate-superfusion evoked NHE1 activity and raised [Na+]i, reported by sodium binding benzofuran isophthalate (SBFI) fluorescence, but EMPA did not ablate this rise. EMPA (10 µM) also had no significant effect on the rate of cytoplasmic [Na+]i rise upon superfusion of Na+-depleted cells with Na+-containing buffers. In Langendorff-perfused mouse, rat and guinea pig hearts, EMPA did not affect [Na+]i at baseline nor pHi recovery following acute acidosis, as measured by 23Na triple quantum filtered NMR and 31P NMR, respectively.
conclusionsOur findings indicate that cardiac NHE1 activity is not inhibited by EMPA (or other SGLT2i's) and EMPA has no effect on [Na+]i over a wide range of concentrations, including the therapeutic dose. Thus, the beneficial effects of SGLT2i's in failing hearts should not be interpreted in terms of actions on myocardial NHE1 or intracellular [Na+].
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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 OpenQuestion graph.