Effects of sodium-glucose co-transporter 2 inhibition with empagliflozin on potassium handling in patients with acute heart failure.
Ontology highlight
ABSTRACT:
SUBMITTER: Beusekamp JC
PROVIDER: S-EPMC8360090 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:AimsSodium-glucose co-transporter 2 (SGLT2) inhibitors improve clinical outcome in patients with heart failure (HF), but the mechanisms behind their beneficial effects are not yet fully understood. We examined the effects of empagliflozin on renal sodium and glucose handling in patients with acute HF.Methods and resultsThis study was a pre-defined sub-study of a double-blind, randomized, placebo-controlled, multicentre study (EMPA-RESPONSE-AHF). Patients were allocated within 24 h of an acute HF admission to either empagliflozin 10 mg/day (n = 40) or placebo (n = 39) for 30 days. Markers of glucose and sodium handling were measured daily during the first 96 h and at day 30. Patients were 76 (range 38-89) years old and 33% had diabetes. The use of loop diuretics during the first 96 h was similar in both groups. Empagliflozin increased fractional glucose excretion with a peak after 24 h (21.8% vs. 0.1%; P < 0.001), without affecting plasma glucose concentration, while fractional sodium and chloride excretion and urinary osmolality remained unchanged (P >0.3 for all). However, empagliflozin increased plasma osmolality (delta osmolality at 72 h: 5 ± 8 vs. 2 ± 5 mOsm/kg; P = 0.049). Finally, there was an early decline in estimated glomerular filtration rate with empagliflozin vs. placebo (-10 ± 12 vs. -2 ± 12 mL/min/1.73 m2 ; P = 0.009), which recovered within 30 days.ConclusionIn patients with acute HF, empagliflozin increased fractional glucose excretion and plasma osmolality, without affecting fractional sodium excretion or urine osmolality and caused a temporary decline in estimated glomerular filtration rate. This suggests that empagliflozin stimulates osmotic diuresis through increased glycosuria rather than natriuresis in patients with acute HF.
| S-EPMC8048437 | biostudies-literature
Project description:Background We determined if the sodium glucose co-transporter 2 inhibitor empagliflozin attenuates pressure overload-induced heart failure in non-diabetic mellitus mice by direct cardiac effects and the mechanisms involved. Methods and Results Male C57BL/6J mice (4-6 months of age) were subjected to sham surgeries or transverse aortic constriction to produce cardiac pressure overload. Two weeks after transverse aortic constriction, empagliflozin (10 mg/kg per day) or vehicle was administered daily for 4 weeks. Empagliflozin increased survival rate and significantly attenuated adverse left ventricle remodeling and cardiac fibrosis after transverse aortic constriction. Empagliflozin also attenuated left ventricular systolic and diastolic dysfunction, evaluated by echocardiography, and increased exercise endurance by 36% in mice with transverse aortic constriction-induced heart failure. Empagliflozin significantly increased glucose and fatty acid oxidation in failing hearts, while reducing glycolysis. These beneficial cardiac effects of empagliflozin occurred despite no significant changes in fasting blood glucose, body weight, or daily urine volume. In vitro experiments in isolated cardiomyocytes indicated that empagliflozin had direct effects to improve cardiomyocyte contractility and calcium transients. Importantly, molecular docking analysis and isolated perfused heart experiments indicated that empagliflozin can bind cardiac glucose transporters to reduce glycolysis, restore activation of adenosine monophosphate-activated protein kinase and inhibit activation of the mammalian target of rapamycin complex 1 pathway. Conclusions Our study demonstrates that empagliflozin may directly bind glucose transporters to reduce glycolysis, rebalance coupling between glycolysis and oxidative phosphorylation, and regulate the adenosine monophosphate-activated protein kinase mammalian target of rapamycin complex 1 pathway to attenuate adverse cardiac remodeling and progression of heart failure induced by pressure-overload in non-diabetic mellitus mice.
| S-EPMC8174202 | biostudies-literature
Project description:PURPOSE OF REVIEW:We highlight the unique properties of the sodium-glucose cotransporter-2 (SGLT-2 inhibitors) which may lend favorably to their efficient integration in the background of other heart failure (HF) therapies. We also discuss the unique aspects of SGLT-2 inhibitor dosing, lack of titration needs, effects on kidney function and electrolytes, diuretic activity, and safety in the high-risk peri-hospitalization window. RECENT FINDINGS:Dapagliflozin was recently approved for the treatment of heart failure with reduced ejection fraction (HFrEF), irrespective of the presence or absence of type 2 diabetes mellitus (T2DM) based on the findings of the pivotal DAPA-HF trial. All SGLT-2 inhibitors are once daily medications with minimal drug-drug interactions and do not require titration (for HF treatment) unlike other HF medications. SGLT-2 inhibitors offer modest weight loss and blood pressure reduction without major adverse effects of hyperkalemia, making it ideal for near-simultaneous initiation with other HF medications, and use in high-risk populations (including older adults). Moreover, SGLT-2 inhibitors appear to afford long-term kidney protection in diverse populations. SGLT-2 inhibitors are the latest class of therapies to demonstrate important clinical benefits among patients with HFrEF, and their pharmacological properties favor ease of use and integration in multi-drug disease-modifying regimens.
| S-EPMC7548057 | biostudies-literature
Project description:Results from cardiovascular outcome trials (CVOT) with 5 different sodium-glucose co-transporter 2 inhibitors (SGLT2i; empagliflozin, canagliflozin, dapagliflozin, ertugliflozin, sotagliflozin), initially developed for their glucose-lowering effect by blocking tubular glucose reabsorption in kidney, have been shown to decrease the risk of heart failure hospitalization (HFH) across a range of patients with and without atherosclerotic cardiovascular disease in patients with type 2 diabetes mellitus (T2DM). Following these CVOT results, SGLT2i (dapagliflozin, empagliflozin, sotagliflozin) also were reported to reduce HFH and cardiovascular death in patients with heart failure with reduced ejection fraction (HFrEF), regardless of existence or absence of T2DM. Ongoing studies have been conducted to evaluate the clinical benefit of SGLT2i (empagliflozin, dapagliflozin) in patients with heart failure with preserved ejection fraction (HFpEF). Although SGLT2i brought us to the entrance of a new era for prevention of HF incidence and worsening of HF, the search for pivotal mechanism of SGLT2i to improve our pharmacological armamentarium should continue in order to protect every HF patient from fatal progression of HF disease. In this review, we summarized the updated clinical evidences on SGLT2i (rather than basic and translational evidence) for reduction of HF risk in T2DM patients and favorable clinical outcomes in both HFrEF and HFpEF patients.
| S-EPMC8112180 | biostudies-literature
Project description:Patients with type 2 diabetes mellitus are at a higher risk of developing heart failure compared with the healthy population. In recent landmark clinical trials, sodium-glucose co-transporter 2 (SGLT2) inhibitor therapies improve blood glucose control and also reduce cardiovascular events and heart failure hospitalisations in patients with type 2 diabetes. Intriguingly, such clinical benefits have also been seen in patients with heart failure in the absence of type 2 diabetes although the underlying mechanisms are not clearly understood. Potential pathways include improved glycaemic control, diuresis, weight reduction and reduction in blood pressure, but none fully explain the observed improvements in clinical outcomes. More recently, novel mechanisms have been proposed to explain these benefits that include improved cardiomyocyte calcium handling, enhanced myocardial energetics, induced autophagy and reduced epicardial fat. We provide an up-to-date review of cardiac-specific SGLT2 inhibitor-mediated mechanisms and highlight studies currently underway investigating some of the proposed mechanisms of action in cardiovascular health and disease.
| S-EPMC8223636 | biostudies-literature
Project description:AimsSodium-glucose co-transporter-2 inhibitors (SGLT2i) have been shown to have a relevant role in the prevention of hospitalizations for heart failure and improvement in the life expectancy of patients with diabetes and outpatients with chronic heart failure (CHF) with reduced left ventricular ejection fraction, independently from the presence of type 2 diabetes mellitus (T2DM). The aim of our study was to evaluate in a real-world population the number of outpatients with CHF who meet the enrolment criteria of the main randomized controlled trials (RCT) published in the last 5 years and consequently identify the percentage of patients who could potential benefit from SGLT2i therapy.Methods and resultsWe retrospectively evaluated all consecutive outpatients referred for CHF. The diagnosis of T2DM was according to the latest European Society of Cardiology Guidelines. Clinical characteristics considered for the enrolment in the RCTs were recorded. We enrolled 515 patients, 384 (75%) of whom had a left ventricular ejection fraction (LVEF) ≤ 40%, 82 (16%) had pre-diabetes, and 187 (36%) had diabetes. Most of the patients with LVEF ≤ 40% met the criteria for the DAPA-HF trial (65%), and this percentage was even higher if the serum level of N-terminal pro-brain natriuretic peptide was not considered. A high percentage of patients with diabetes and LVEF > 40% met the criteria for the DECLARE (39%), CANVAS (47%), and EMPA-REG (30%) trials. Patients meeting the enrolment criteria of RCTs evaluating SGLT2i were also characterized by a high risk of heart failure events during follow-up.ConclusionsIn spite of a low number of patients actually treated with SGLT2i, we observed that a high prevalence of patients with CHF met the clinical characteristics of RCTs that have demonstrated a beneficial effect of SGLT2i.
| S-EPMC8318395 | biostudies-literature
Project description:Heart failure is a shared chronic phase of many cardiac diseases and its prevalence is on the rise globally. Previous large-scale cardiovascular outcomes trials of sodium.glucose co-transporter 2 (SGLT2) inhibitors in patients with type 2 diabetes (T2D) have suggested that these agents may help to prevent primary and secondary hospitalisation due to heart failure and cardiovascular death in these patients. Data from the Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure (DAPA-HF) and Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction (EMPEROR-Reduced) have demonstrated the positive clinical impact of SGLT2 inhibition in patients with heart failure with reduced ejection fraction both with and without T2D. These data have led to the approval of dapagliflozin for the treatment of patients with heart failure with reduced ejection fraction, irrespective of T2D status. This article reviews the latest data reported from the DAPA-HF and EMPEROR-Reduced trials and their clinical implications for the treatment of patients with heart failure.
| S-EPMC7689869 | biostudies-literature
Project description:AimsTreatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors improves outcomes in patients with chronic heart failure (HF) with reduced ejection fraction. There is limited experience with the in-hospital initiation of SGLT2 inhibitors in patients with acute HF (AHF) with or without diabetes. EMPULSE is designed to assess the clinical benefit and safety of the SGLT2 inhibitor empagliflozin compared with placebo in patients hospitalized with AHF.MethodsEMPULSE is a randomized, double-blind, parallel-group, placebo-controlled multinational trial comparing the in-hospital initiation of empagliflozin (10 mg once daily) with placebo. Approximately 500 patients admitted for AHF with dyspnoea, signs of fluid overload, and elevated natriuretic peptides will be randomized 1:1 stratified to HF status (de-novo and decompensated chronic HF) to either empagliflozin or placebo at approximately 165 sites across North America, Europe and Asia. Patients will be enrolled regardless of ejection fraction and diabetes status and will be randomized during hospitalization and after stabilization (between 24 h and 5 days after admission), with treatment continued up to 90 days after initiation. The primary outcome is clinical benefit at 90 days, consisting of a composite of all-cause death, HF events, and ≥5 point change from baseline in Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), assessed using a 'win-ratio' approach. Secondary outcomes include assessments of safety, change in KCCQ-TSS from baseline to 90 days and change in natriuretic peptides from baseline to 30 days.ConclusionThe EMPULSE trial will evaluate the clinical benefit and safety of empagliflozin in patients hospitalized for AHF.
| S-EPMC8358952 | biostudies-literature
Project description:AimsExplore the efficacy, safety and tolerability of the dual sodium-glucose cotransporter (SGLT) 1 and 2 inhibitor, licogliflozin in patients with type-2 diabetes mellitus (T2DM) and heart failure.MethodsThis multicentre, parallel-group phase IIA study randomized 125 patients with T2DM and heart failure (New York Heart Association II-IV; plasma N-terminal pro b-type natriuretic peptide [NT-proBNP] >300 pg/mL) to licogliflozin (2.5 mg, 10 mg, 50 mg) taken at bedtime, empagliflozin (25 mg) or placebo (44 patients completed the study). The primary endpoint was change from baseline in NT-proBNP after 12 weeks. Secondary endpoints included change from baseline in glycated haemoglobin, fasting plasma glucose, weight, blood pressure, fasting lipid profile, high-sensitivity c-reactive protein, and safety and tolerability.ResultsLicogliflozin 10 mg for 12 weeks significantly reduced NT-proBNP vs placebo (Geometric mean ratio 0.56 [95% confidence interval: 0.33, 0.95], P = .033). A trend was observed with 50 mg licogliflozin (0.64 [95% confidence interval: 0.40, 1.03], P = .064), with no difference between licogliflozin and empagliflozin. The largest numerical decreases in glycated haemoglobin were with licogliflozin 50 mg (-0.58 ± 0.34%) and empagliflozin (-0.44 ± 1.18%) vs placebo (-0.04 ± 0.91%). The reduction in body weight was similar with licogliflozin 50 mg (-2.15 ± 2.40 kg) and empagliflozin (-2.25 ± 1.89 kg). A numerical reduction in systolic blood pressure was seen with licogliflozin 50 mg (-9.54 ± 16.88 mmHg) and empagliflozin (-6.98 ± 15.03 mmHg) vs placebo (-2.85 ± 11.97 mmHg). Adverse events (AEs) were mild, including hypotension (6.5%), hypoglycaemia (8.1%) and inadequate diabetes control (1.6%). The incidence of diarrhoea (4.9%) was lower than previously reported.ConclusionThe reduction in NT-proBNP with licogliflozin suggests a potential benefit of SGLT1 and 2 inhibition in patients with T2DM and heart failure.
| S-EPMC7318993 | biostudies-literature
Project description:Epithelial glucose transport is accomplished by Na+ -glucose co-transporters, SGLT1 and SGLT2. In the intestine, uptake of dietary glucose is for its majority mediated by SGLT1, and humans with mutations in the SGLT1 gene show glucose/galactose malabsorption. In the kidney, both transporters, SGLT1 and SGLT2, are expressed and recent studies identified that SGLT2 mediates up to 97% of glucose reabsorption. Humans with mutations in the SGLT2 gene show familial renal glucosuria. In the last three decades, significant progress was made in understanding the physiology of these transporters and their potential as therapeutic targets. Based on the structure of phlorizin, a natural compound acting as a SGLT1/2 inhibitor, initially several SGLT2, and later SGLT1 and dual SGLT1/2 inhibitors have been developed. Interestingly, SGLT2 knockout or treatment with SGLT2 selective inhibitors only causes a fractional glucose excretion in the magnitude of ∼60%, an effect mediated by up-regulation of renal SGLT1. Based on these findings the hypothesis was brought forward that dual SGLT1/2 inhibition might further improve glycaemic control via targeting two distinct organs that express SGLT1: the intestine and the kidney. Of note, SGLT1/2 double knockout mice completely lack renal glucose reabsorption. This review will address the rationale for the development of SGLT1 and dual SGLT1/2 inhibitors and potential benefits compared to sole SGLT2 inhibition.
| S-EPMC6516085 | biostudies-literature