Impact Of Empagliflozin Research Articles

Mechanism of the cardioprotective effect of empagliflozin on diabetic nephropathy mice based on the basis of proteomics

Diabetic nephropathy affects a significant proportion of individuals with diabetes, and its progression often leads to cardiovascular disease and infections before the need for renal replacement therapy arises. Empagliflozin has been shown to have various protective effects in cardiovascular disease studies, such as improving diabetic myocardial structure and function, and reducing myocardial oxidative stress. However, the impact of empagliflozin on cardiac protein expression and signaling pathways has not been comprehensively analyzed. To address this gap, we conducted proteome analysis to identify specific protein markers in cardiac tissue from the diabetes model group, including Myh7, Wdr37, Eif3k, Acot1, Acot2, Cat, and Scp2, in cardiac tissue from the diabetes model group. In our drug model, empagliflozin primarily modulates the fat-related metabolic signaling pathway within the heart. Empagliflozin downregulated the protein expression levels of ACOX1, ACADVL and CPT1A in the model group. Overall, our findings demonstrate that empagliflozin provides cardiac protection by targeting metabolic signaling pathways, particularly those related to fat metabolism. Moreover, the identification of cardiac biomarkers in a mouse model of diabetic nephropathy lays the foundation for further exploration of disease biomarkers in cardiac tissue.

Impact of empagliflozin on cardiac structure and function assessed by echocardiography after myocardial infarction: a post-hoc sub-analysis of the emmy trial

Abstract Background Empagliflozin administered after acute myocardial infarction proofed to improve cardiometabolic parameters and biomarkers, but the impact on cardiac function is still largely unknown. The aim of this post-hoc echocardiographic sub-analysis of the EMMY trial was to provide in-depth echocardiographic analysis on the effects of empagliflozin versus placebo on standard and novel echocardiographic structural and functional parameters after acute myocardial infarction. Methods In this post-hoc analysis of the EMMY trial a subset of 313 patients (157 empagliflozin vs. 156 placebo) was enrolled for post-processing analysis of echocardiographic structural and functional parameters. On top of two-dimensional and Doppler parameters, myocardial deformation analyses were performed to assess ventricular and atrial strain values. Results Left ventricular volumes showed significant differences in favor of empagliflozin over the course of the trial (change in left ventricular end-diastolic volume median [interquartile range] 8 [−3;19]% versus 13 [0;29]%, p = 0.048; left ventricular end-systolic volume −3 [−15;12]% versus 4 [−12;18]%, p = 0.044). This effect persisted after adjusting for baseline values, age, and sex. Left ventricular systolic and diastolic function overall improved over the course of the trial and parameters for diastolic function showed a distinct trend between groups but did not meet statistical significance in this cohort. Conclusion In this post-hoc analysis among patients with acute myocardial infarction, treatment with empagliflozin resulted in a significant beneficial effect on left ventricular end-diastolic and end-systolic volume, without significantly improving left ventricular or right ventricular functional parameters compared to placebo after 26 weeks. ClinicalTrials.gov registration NCT03087773. Graphical abstract

Impact of Empagliflozin on the Outcomes of β-Thalassemia Major in Patients With Type 2 Diabetes Mellitus: The THALEMPA Observational Study.

Beta-thalassemia major (β-TM) is a genetic disorder characterized by ineffective erythropoiesis and chronic hemolytic anemia, necessitating lifelong blood transfusions and leading to severe complications. This study, termed THALEMPA by the authors, investigated the effect of empagliflozin (EMPA) on β-TM outcomes in patients with type 2 diabetes mellitus (T2DM), focusing on disease severity and associated complications of iron overload and hyperuricemia. This study conducted a single-center prospective observational investigation involving adults diagnosed with β-TM and T2DM. A total of 20 carefully selected patients were stratified into two groups based on their medical condition: the EMPA group, receiving 10 mg of empagliflozin, and a control group, receiving standard care. This focused cohort size was chosen to ensure a detailed, in-depth analysis of the treatment effects within this specific patient population. Over three months, both groups were closely monitored for β-TM outcomes. The study assessed β-TM severity parameters such as hemoglobin levels, blood transfusion frequency, aspartate aminotransferase (AST), alanine aminotransferase (ALT), left ventricular ejection fraction percentage, and spleen size. Additionally, β-TM complications were evaluated through serum ferritin and uric acid levels. Our analysis revealed that EMPA increased hemoglobin levels by up to 0.56 g/dL compared to baseline (P< 0.05). Liver enzyme levels significantly improved with EMPA by the third month. AST and ALT decreased by 36.22% and 33.36%, respectively, from baseline levels (P< 0.05), highlighting EMPA's potential benefits for β-TM severity. Serum ferritin and uric acid levels decreased by 27.93% and 21.29%, respectively, over three months on EMPA (P< 0.05). However, other parameters did not show significant changes post-EMPA. This study demonstrates the significant impact of EMPA treatment over three months on β-TM patients with T2DM, evidenced by notable improvements in hemoglobin levels and reductions in liver enzymes, as well as in complications related to iron overload and hyperuricemia. Future research should confirm these benefits over longer durations and assess broader patient outcomes such as quality of life.

The Impact of Empagliflozin on Renal Function and Kidney Injury Markers in Patients with Diabetic Nephropathy

Background: Diabetic nephropathy affects approximately 50% of type 2 diabetes patients. Early detection of kidney disease is crucial to reducing the deterioration of renal function. Reversing microalbuminuria towards normal showed beneficial effects in delaying the onset of renal impairment or even reversing the progression of the disease. Recently, empagliflozin, a sodium/glucose cotransporter-2 inhibitor, has received attention for its anti-inflammatory and reno-cardioprotective effects. Objective: This interventional open-label randomized clinical trial aimed to evaluate the clinical outcome of empagliflozin as an add-on therapy for renal function parameters and other injury markers in type 2 diabetic nephropathy patients. Methods: The study enrolled twenty-one type 2 diabetic patients with nephropathy and nineteen without nephropathy. Each group received empagliflozin 10 mg/day for 16 weeks as an add-on to the traditional treatment. Blood and urine samples were collected at baseline and at week 16 to evaluate the glycemic status, renal function, tubular injury markers, and inflammatory and oxidative stress markers. Results: After 16 weeks, empagliflozin significantly reduced glycated hemoglobin A1c and urinary albumin/creatinine ratios in the nephropathy group. Compared with the non-nephropathy group, empagliflozin showed a significant increase in serum creatinine and a significant decrease in eGFRcr. Empagliflozin significantly reduced serum kidney injury molecule-1, cystatin C, interleukin-18, c-reactive protein, and malondialdehyde in both groups. Conclusions: Adding empagliflozin to the traditional oral antidiabetic drugs in diabetic nephropathy improved albuminuria with a mild increment in serum creatinine. Empagliflozin also effectively reduced renal injury markers, as well as inflammatory and oxidative stress markers.

Sodium-Glucose Co-Transporter-2 Inhibitor Empagliflozin Attenuates Sorafenib-Induced Myocardial Inflammation and Toxicity.

Environmental antineoplastics such as sorafenib may pose a risk to humans through water recycling, and the increased risk of cardiotoxicity is a clinical issue in sorafenib users. Thus, developing strategies to prevent sorafenib cardiotoxicity is an urgent work. Empagliflozin, as a sodium-glucose co-transporter-2 (SGLT2) inhibitor for type 2 diabetes control, has been approved for heart failure therapy. Still, its cardioprotective effect in the experimental model of sorafenib cardiotoxicity has not yet been reported. Real-time quantitative RT-PCR (qRT-PCR), immunoblot, and immunohistochemical analyses were applied to study the effect of sorafenib exposure on cardiac SGLT2 expression. The impact of empagliflozin on cell viability was investigated in the sorafenib-treated cardiomyocytes using Alamar blue assay. Immunoblot analysis was employed to delineate the effect of sorafenib and empagliflozin on ferroptosis/proinflammatory signaling in cardiomyocytes. Ferroptosis/DNA damage/fibrosis/inflammation of myocardial tissues was studied in mice with a 28-day sorafenib ± empagliflozin treatment using histological analyses. Sorafenib exposure significantly promoted SGLT2 upregulation in cardiomyocytes and mouse hearts. Empagliflozin treatment significantly attenuated the sorafenib-induced cytotoxicity/DNA damage/fibrosis in cardiomyocytes and mouse hearts. Moreover, GPX4/xCT-dependent ferroptosis as an inducer for releasing high mobility group box 1 (HMGB1) was also blocked by empagliflozin administration in the sorafenib-treated cardiomyocytes and myocardial tissues. Furthermore, empagliflozin treatment significantly inhibited the sorafenib-promoted NFκB/HMGB1 axis in cardiomyocytes and myocardial tissues, and sorafenib-stimulated proinflammatory signaling (TNF-α/IL-1β/IL-6) was repressed by empagliflozin administration. Finally, empagliflozin treatment significantly attenuated the sorafenib-promoted macrophage recruitments in mouse hearts. In conclusion, empagliflozin may act as a cardioprotective agent for humans under sorafenib exposure by modulating ferroptosis/DNA damage/fibrosis/inflammation. However, further clinical evidence is required to support this preclinical finding.

Empagliflozin Improves Diastolic Function in HFpEF by Restabilizing the Mitochondrial Respiratory Chain.

Clinical studies demonstrated beneficial effects of sodium-glucose-transporter 2 inhibitors on the risk of cardiovascular death in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes for cardioprotection remain unclear. The present study focused on the impact of empagliflozin (Empa) on myocardial function in a rat model with established HFpEF and analyzed underlying molecular mechanisms. Obese ZSF1 (Zucker fatty and spontaneously hypertensive) rats were randomized to standard care (HFpEF, n=18) or Empa (HFpEF/Empa, n=18). ZSF1 lean rats (con, n=18) served as healthy controls. Echocardiography was performed at baseline and after 4 and 8 weeks, respectively. After 8 weeks of treatment, hemodynamics were measured invasively, mitochondrial function was assessed and myocardial tissue was collected for either molecular and histological analyses or transmission electron microscopy. In HFpEF Empa significantly improved diastolic function (E/é: con: 17.5±2.8; HFpEF: 24.4±4.6; P<0.001 versus con; HFpEF/Empa: 19.4±3.2; P<0.001 versus HFpEF). This was accompanied by improved hemodynamics and calcium handling and by reduced inflammation, hypertrophy, and fibrosis. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation. Cardiac mitochondrial respiration was significantly impaired in HFpEF but restored by Empa (Vmax complex IV: con: 0.18±0.07 mmol O2/s/mg; HFpEF: 0.13±0.05 mmol O2/s/mg; P<0.041 versus con; HFpEF/Empa: 0.21±0.05 mmol O2/s/mg; P=0.012 versus HFpEF) without alterations of mitochondrial content. The expression of cardiolipin, an essential stability/functionality-mediating phospholipid of the respiratory chain, was significantly decreased in HFpEF but reverted by Empa (con: 15.9±1.7 nmol/mg protein; HFpEF: 12.5±1.8 nmol/mg protein; P=0.002 versus con; HFpEF/Empa: 14.5±1.8 nmol/mg protein; P=0.03 versus HFpEF). Transmission electron microscopy revealed a reduced size of mitochondria in HFpEF, which was restored by Empa. The study demonstrates beneficial effects of Empa on diastolic function, hemodynamics, inflammation, and cardiac remodeling in a rat model of HFpEF. These effects were mediated by improved mitochondrial respiratory capacity due to modulated cardiolipin and improved calcium handling.

Left Ventricular Function, Congestion, and Effect of Empagliflozin on Heart Failure Risk After Myocardial Infarction

BackgroundEmpagliflozin reduces the risk of heart failure (HF) hospitalizations but not all-cause mortality when started within 14 days of acute myocardial infarction (AMI). ObjectivesThis study sought to evaluate the association of left ventricular ejection fraction (LVEF), congestion, or both, with outcomes and the impact of empagliflozin in reducing HF risk post-AMI. MethodsIn the EMPACT-MI (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction) trial, patients were randomized within 14 days of an AMI complicated by either newly reduced LVEF<45%, congestion, or both, to empagliflozin (10 mg daily) or placebo and were followed up for a median of 17.9 months. ResultsAmong 6,522 patients, the mean baseline LVEF was 41 ± 9%; 2,648 patients (40.6%) presented with LVEF <45% alone, 1,483 (22.7%) presented with congestion alone, and 2,181 (33.4%) presented with both. Among patients in the placebo arm of the trial, multivariable adjusted risk for each 10-point reduction in LVEF included all-cause death or HF hospitalization (HR: 1.49; 95% CI: 1.31-1.69; P < 0.0001), first HF hospitalization (HR: 1.64; 95% CI: 1.37-1.96; P < 0.0001), and total HF hospitalizations (rate ratio [RR]: 1.89; 95% CI: 1.51-2.36; P < 0.0001). The presence of congestion was also associated with a significantly higher risk for each of these outcomes (HR: 1.52, 1.94, and RR: 2.03, respectively). Empagliflozin reduced the risk for first (HR: 0.77; 95% CI: 0.60-0.98) and total (RR: 0.67; 95% CI: 0.50-0.89) HF hospitalizations, irrespective of LVEF or congestion, or both. The safety profile of empagliflozin was consistent across baseline LVEF and irrespective of congestion status. ConclusionsIn patients with AMI, the severity of left ventricular dysfunction and the presence of congestion was associated with worse outcomes. Empagliflozin reduced first and total HF hospitalizations across the range of LVEF with and without congestion. (Trial to Evaluate the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction [EMPACT-MI]; NCT04509674)

Impact of Empagliflozin on the Kidneys of Male Albino Rats

Impact of Empagliflozin on the Kidneys of Male Albino Rats

Baseline characteristics of patients enrolled in the EMPACT-MI trial

Abstract Background Empagliflozin has been shown to reduce the risk of adverse cardiovascular (CV) outcomes in patients with type 2 diabetes (T2DM) and in those with heart failure (HF). The impact of empagliflozin in post-acute myocardial infarction (AMI) patients is unknown. Methods and Results The Study to Test the Effect of Empagliflozin on Hospitalization For Heart Failure And Mortality In Patients With Acute Myocardial Infarction (EMPACT-MI) trial screened 6610 participants with AMI and 6522 were randomized to empagliflozin or placebo in addition to standard of care. Patients were eligible for enrollment if they had no history of HF, had been hospitalized with a AMI and had either acute signs or symptoms of congestion that required treatment, and/or a newly depressed LVEF&amp;lt;45%. Patients were also required to have at least one additional risk factor (enrichment criterion). The median (interquartile range) age of trial population was 64 (56-71) years and 75.1% were male. Major comorbidities included hypertension (69.1%), atrial fibrillation (10.9%), prior myocardial infarction (13.0%), and type 2 diabetes (31.7%). The majority (74.3%) of patients presented with an ST elevation myocardial infarction. Overall, 56.9% of patients randomized had acute signs or symptoms of congestion that required treatment, and 78.3% had newly developed left ventricular systolic dysfunction with ejection fraction &amp;lt;45%. Key characteristics of EMPACT-MI patient population are presented on the figure 1. Conclusion EMPACT-MI has randomized 6522 patients with acute MI. EMPACT-MI will establish the benefit and risks of empagliflozin in these patients.

Abstract 17725: Prognostic Implications and the Impact of Empagliflozin on Bone Morphogenetic Protein-10 in Heart Failure: Results from the EMPEROR Program

Background: Bone morphogenetic protein (BMP)-10 is upregulated in response to cardiac injury and exerts a protective role via activating transforming growth factor β/Smad and STAT3-pathways preserving normal cardiac function by inhibiting cell death and fibrosis. Aim: To assess association of baseline characteristics and prognostic significance of BMP-10 in patients with heart failure (HF) with reduced or preserved ejection fraction, and the effect of empagliflozin on BMP-10 level. Methods: Serum BMP-10 (Elecsys®, Roche Diagnostics) was assessed in 1127 patients from the EMPEROR-Reduced and Preserved trials, categorized by tertiles of baseline BMP-10 (&lt;2.35; ≥2.35-&lt;3.11; ≥3.11 ng/mL). Results: Median baseline BMP-10 was 2.71 ng/mL. Patients in higher tertiles tended to be older, women, NYHA class III-IV, with obesity, atrial fibrillation, and worse renal function (all P&lt;0.05). Baseline BMP-10 level correlated with N-terminal pro B-type natriuretic peptides and high-sensitivity troponin T levels (Spearman rho=0.41, 0.26 respectively). Higher baseline BMP-10 was associated with increased risk for adverse outcomes ( Table 1 ). For each 2-fold increase in BMP-10, the adjusted hazard ratio (HR) for cardiovascular death (CV) or HF hospitalization was 2.85 (95% CI 1.99, 4.09, P&lt;0.0001). Empagliflozin treatment was associated with reduction in BMP-10 at week 12 (adjusted gMean ratio 0.94 [0.91-0.97], P&lt;0.001) but not week 52 (1.00 [0.96-1.04], P=0.86). Empagliflozin reduced the risk of CV death or HF hospitalization, particularly for patients at highest baseline BMP-10 level (&lt;1 st tertile HR 1.03 [0.56-1.88]; ≥1 st and &lt;2 nd tertile HR 0.74 [0.40-1.35]; ≥2 nd tertile HR 0.61 [0.40-0.92], P-trend=0.15). Conclusion: BMP-10 levels were associated with worse disease severity and outcomes in patients with HF. Empagliflozin was associated with reduction of BMP-10 at week 12. The benefit of empagliflozin on outcomes was more pronounced with higher BMP-10 levels.

Baseline characteristics of patients enrolled in the EMPACT-MI trial.

Empagliflozin has been shown to reduce the risk of adverse cardiovascular outcomes in patients with type 2 diabetes and in those with heart failure. The impact of empagliflozin in post-acute myocardial infarction (AMI) patients is unknown. The Study to Test the Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients with Acute Myocardial Infarction (EMPACT-MI) trial screened 6610 participants with AMI and randomized 6522 to empagliflozin or placebo in addition to standard of care. The median (interquartile) age was 64 (56-71) years and 75.1% of patients were male. Major comorbidities included hypertension (69.1%), type 2 diabetes (31.7%), prior myocardial infarction (13.0%), and atrial fibrillation (10.9%). The majority (74.3%) of patients presented with an ST-elevation myocardial infarction. Overall, 56.9% of patients had acute signs or symptoms of congestion requiring treatment and 78.3% had left ventricular systolic dysfunction with ejection fraction <45%. Clinical characteristics, including baseline demographics, rates of revascularization, and cardiovascular medications at discharge were largely comparable to recent trials of the post-AMI population. The EMPACT-MI trial will establish the benefit and risks of empagliflozin treatment in patients with AMI.

Health status across major subgroups of patients with heart failure and preserved ejection fraction.

There are limited data on health status and changes in it over time across major subgroups of patients with heart failure and preserved ejection fraction (HFpEF), including ejection fraction spectrum, age, sex, region, body mass index (BMI), and comorbidities including diabetes, chronic kidney disease (CKD), anaemia, and atrial fibrillation/flutter. In the EMPEROR-Preserved trial, the Kansas City Cardiomyopathy Questionnaire (KCCQ) was assessed at baseline, 12, 32 and 52 weeks. Determinants of baseline KCCQ score and change over time, and the impact of empagliflozin on KCCQ scores were studied in specified subgroups. A Cox model was used to assess the association between 5- and 10-point increase and 5-point decrease in KCCQ score from baseline to week 12 and later outcomes. Among 2979 participants in the placebo arm, mean KCCQ clinical summary score (CSS) was 70.7 (20.8). Older age, female sex, BMI, anaemia, and a history of diabetes, and CKD were associated with worse scores. KCCQ-CSS score improved during follow-up; patients with atrial fibrillation/flutter at enrollment (p trend = 0.014) and CKD (p trend < 0.001) had less improvement. A 5-point increase in KCCQ-CSS at week 12 was associated with lower risk of cardiovascular death or heart failure hospitalization (5%), cardiovascular death (8%), and first heart failure hospitalization (4%) subsequently. A similar trend was seen with KCCQ total symptom score (TSS) and overall summary score (OSS). Empagliflozin improved KCCQ-CSS, -TSS and -OSS scores similarly across subgroups studied except for greater improvement in patients with the highest BMI (p trend = 0.153, 0.08 and 0.078, respectively). Health status in patients with HFpEF is impaired, especially in elderly, women, and those with obesity and comorbidities. Empagliflozin improved health status among all key subgroups studied with a greater effect in obese patients.

CHAnges in Diuretic Medication Prescribing and Surrogate Laboratory Parameters After Initiating EmpagliflOziN in Veterans (CHAMPION Cohort Study).

Sodium-glucose cotransporter type 2 inhibitors have evolved into a novel drug class utilized for reductions in cardiovascular risk and heart failure hospitalization. We aimed to describe the impact of sodium-glucose cotransporter type 2 inhibitors on diuretic prescribing patterns and intermediate laboratory outcomes in patients with and without diuretic use. This retrospective cohort study included patients taking empagliflozin as of 1 July, 2021. Patients were assigned to the intervention group if prescribed a diuretic concomitantly or a control group otherwise. The primary outcome was the impact of empagliflozin on diuretic prescribing (i.e., no change, discontinuation, decrease, increase). Secondary outcomes were change in weight, hemoglobin A1c, estimated glomerular filtration rate, hemoglobin, hematocrit, blood pressure, and electrolytes at 90 and 180 days. Mean differences were compared using the t-test between groups or the paired t-test within groups. Patients without diuretic use were matched 1:1 to patients taking diuretics using propensity scores. This study included 1189 patients: 750 in the control group and 439 in the intervention group. After propensity score matching, baseline characteristics were well balanced. Of the 439 patients in the intervention group, 118 had changes in the diuretic regimen. There were 131 changes: 109 (83.2%) discontinuations, 13 (9.92%) decreases, and nine (6.87%) increases. The mean furosemide equivalent loop dose was reduced after empagliflozin initiation (50.62 mg vs 43.13 mg; p < 0.001). Among all patients, there was a decrease in weight (p = 0.01), estimated glomerular filtration rate (p < 0.001), and hemoglobin A1c (p < 0.001). There was an increase in hemoglobin (p < 0.001), hematocrit (p < 0.001), and magnesium (p < 0.001). In the propensity score-matched cohort, there was a significant reduction from baseline in mean weight in the intervention group compared with the control group (p < 0.001). This hypothesis-generating study suggests that sodium-glucose cotransporter type 2 inhibitors may lower diuretic requirements, further supported by a reduction in weight in the intervention cohort.

Impact of Empagliflozin on myocardial metabolism and mitochondrial function in a cardiometabolic obese rat model of HFpEF

Impact of Empagliflozin on myocardial metabolism and mitochondrial function in a cardiometabolic obese rat model of HFpEF

Take an OSA pill and call me in the morning.

Take an OSA pill and call me in the morning.

Impact of empagliflozin on left atrial mechanical and conduction functions in patients with type 2 diabetes mellitus.

Empagliflozin, an oral anti-diabetic drug that inhibits the sodium-dependent glucose co-transporter 2 (SGLT2), has pleiotropic effects on the myocardium. The aim of the study is to investigate the effect of empagliflozin on atrial electromechanical delay (AEMD) and the left atrial (LA) mechanical functions in patients with type 2 diabetes mellitus (DM). In total 62 patients (40.3% female, mean age 50.5 ± 8.6 years old) with type 2 DM were enrolled to the study. Participants were used a SGLT2 inhibitor (empagliflozin 10-25 mg/daily) for 6months. Patients were examined initially and after 6 months with echocardiography. LA volume was recorded, atrial conduction times were measured using tissue Doppler imaging (TDI). No significant change was observed in LA volumes (maximal, minimal, and presystolic), total emptying and passive emptying volume at the end of 6months; however, there was a significant decrease in active emptying volume (8.3 ± 2.9ml/m2 vs. 7.9 ± 2.9ml/m2 , p=0.04). The posteroanterior lateral, septal, and tricuspid conduction times significantly decreased after the empagliflozin treatment. The decrease in right inter-AEMD was statistically significant (13.25 ± 10.21 ms vs. 10.85 ± 9.14 ms, p=0.011). The changes in inter-AEMD were found to be correlated with the changes in LA active emptying volume (r=0.408). Empagliflozin may enhance the structure and electrical conductions of the atrium and may prevent DM patients from DM-2-related functional disorder and arrhythmia.

LEFT VENTRICULAR MASS PREDICTS CARDIAC REVERSE REMODELING IN PATIENTS TREATED WITH EMPAGLIFLOZIN: AN EXPLORATORY SUB-ANALYSIS OF THE EMPA-HEART CARDIOLINK-6 RANDOMIZED CONTROLLED TRIAL

LEFT VENTRICULAR MASS PREDICTS CARDIAC REVERSE REMODELING IN PATIENTS TREATED WITH EMPAGLIFLOZIN: AN EXPLORATORY SUB-ANALYSIS OF THE EMPA-HEART CARDIOLINK-6 RANDOMIZED CONTROLLED TRIAL

The impact of empagliflozin on cardiac physiology and fibrosis early after myocardial infarction in non-diabetic rats

BackgroundMyocardial fibrosis is a multistep process, which results in collagen deposition in the injured muscle. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor (SGLT2i), decreases cardiovascular events risk. Little is known on the effects of empagliflozin in non-diabetic patients early post myocardial infarction.MethodsFourteen non-diabetic rats underwent myocardial infarction induction, and treated or not (control)immediately after myocardial infarction by daily empagliflozin (30 mg/kg/day). We evaluated cardiac function at baseline, 2 and 4 weeks after myocardial infarction by echocardiography, and prior to sacrifice by Millar pressure–volume system. We performed histological and biochemical evaluation of fibrosis and humoral factors promoting fibrosis.ResultsBaseline ejection fractions were 69.9 ± 5.3% and 76.4 ± 5.4%, and dropped to final values of 40.1 ± 5.8% and 39.4 ± 5.4% in the control and empagliflozin groups, respectively (P < 0.001 vs. baseline, P > 0.05 between groups). Collagen deposition, measured as collagen volume fraction, was higher in both the scar and the remote cardiac areas of the control group 79.1 ± 6.2% and 4.6 ± 2.5% for control, and 53.8 ± 5.4% and 2.5 ± 1.3% for empagliflozin group, respectively (P < 0.05 for each). Remote cardiac muscle collagen, measured by hydroxyproline, was 4.1 ± 0.4 μg/μl and 3.6 ± 0.2 μg/μl (P = 0.07). TGF-β1 and Smad3 expression decreased by empagliflozin—18.73 ± 16.32%, 9.16 ± 5.69% and 16.32 ± 5.4%, 7.00 ± 5.28% in the control and empagliflozin groups, respectively (P < 0.05).Conclusion/interpretationEmpagliflozin administered early after myocardial infarction reduce myocardial fibrosis and inhibit the TGF-β1/Smad3 fibrotic pathway, probably prior to exerting any hemodynamic or physiological effect.

Empagliflozin impairs smooth muscle cell proliferation, accelerates endothelial regeneration, and prevents neointima formation by altered expression of the vasoactive peptide apelin

Abstract Background Empagliflozin, an inhibitor of the sodium glucose co-transporter 2 (SGLT2), developed as an anti-diabetic agent exerts additional beneficial effects on heart failure outcomes in patients with type 2 diabetes mellitus at high cardiovascular risk. However, the effect of empagliflozin on vascular cell function and vascular remodeling processes remain largely elusive. Methods/Results Immunocytochemistry and immunoblotting revealed SGLT2 to be expressed in human diabetic and non-diabetic smooth muscle (SMC) and endothelial cells (EC) as well as in murine femoral arteries. In vitro, empagliflozin significantly reduced serum-induced proliferation and migration of human diabetic and non-diabetic SMCs in a dose-dependent manner without any toxic or apoptotic effects. In contrast, empagliflozin significantly increased the cell count and migrational capacity of human diabetic ECs, but not of human non-diabetic ECs. In vivo, therapeutic application of empagliflozin (225 mg/kg medicated diet) resulted in a significantly reduced number of Ki-67+ proliferating neointimal cells in response to femoral artery wire-injury in C57BL/6J mice. Empagliflozin furthermore prevented subsequent neointima formation (luminal stenosis 91.2% vs. 80.6% at 21 days; P&amp;lt;0.05). Comparable effects of empagliflozin were observed in a streptozocin-induced diabetic model of apolipoprotein E−/− mice. Conclusive to the in vitro-results, re-endothelialization was not significantly affected in C57BL/6 mice (non-reendothelialized distance 2.57 mm vs. 2.3 mm; P=0.07), but even significantly improved in diabetic mice after treatment with empagliflozin (3.1 mm vs. 2.58 mm; P&amp;lt;0.001) assessed by Evan's Blue staining 3 days after electric denudation of the murine carotid artery. Microarray analysis of human SMCs identified the vasoactive peptide apelin to be decisively regulated in response to empagliflozin treatment. Further pathway analysis exhibited apelin to prevent SMC proliferation by de-phosphorylation of Akt and to augment EC proliferation by phosphorylation of p38 MAPK. Conclusion These data document the functional impact of empagliflozin on vascular SMCs and ECs for the first time. Empagliflozin significantly reduces serum-induced proliferation and migration of SMCs in vitro and prevented neointima formation in vivo, while augmenting EC proliferation in vitro and re-endothelialization in vivo after vascular injury. Thus, empagliflozin holds promise to exert favorable effects on vascular healing, and to prevent neointima formation following vascular injury in diabetic and non-diabetic patients. Funding Acknowledgement Type of funding source: Public Institution(s). Main funding source(s): Hannover Medical School, Martin-Luther-University Halle-Wittenberg

The Impact of Empagliflozin on Obstructive Sleep Apnea and Cardiovascular and Renal Outcomes: An Exploratory Analysis of the EMPA-REG OUTCOME Trial.

To explore the effects of empagliflozin on the incidence of obstructive sleep apnea (OSA) and its effects on metabolic, cardiovascular (CV), and renal outcomes among participants with or without OSA in the EMPA-REG OUTCOME trial. Participants with diabetes and CV disease were randomized to empagliflozin (10 and 25 mg) or placebo daily in addition to standard of care. OSA was assessed by investigator report using Medical Dictionary for Regulatory Activities version 18.0, and CV outcomes were independently adjudicated. Analyses were performed using multivariable-adjusted Cox regression models. OSA was reported in 391 of 7,020 (5.6%) participants at baseline. Those with OSA were more likely to be male (83% vs. 71%) and to have moderate to severe obesity (BMI ≥35 kg/m2; 55% vs. 18%). Over a median of 3.1 years, empagliflozin had similar placebo-adjusted reductions in HbA1c, waist circumference, and systolic blood pressure, regardless of OSA status, but a larger effect on weight (adjusted mean ± SE difference at week 52: OSA vs. no OSA -2.9 ± 0.5 vs. -1.9 ± 0.1 kg). Incidence of 3-point major adverse CV events, CV death, heart failure hospitalization, and incident or worsening nephropathy in the placebo group was 1.2- to 2.0-fold higher for those with baseline OSA compared with those without. Empagliflozin significantly reduced the risk for outcomes regardless of OSA status (P-interaction all >0.05). Fifty patients reported a new diagnosis of OSA through 7 days after medication discontinuation, and this occurred less often with empagliflozin treatment (hazard ratio 0.48 [95% CI 0.27, 0.83]). In EMPA-REG OUTCOME, participants with OSA had greater comorbidity and higher frequency of CV and renal events. Empagliflozin had favorable effects on risk factors and CV and renal outcomes regardless of preexisting OSA and may also reduce the risk for new-onset OSA.