Effects Of Empagliflozin Research Articles

Anti-anginal effects of empagliflozin in patients with type 2 diabetic and refractory angina; A randomized, double-blind placebo-controlled trial (EMPT-angina trial)

Anti-anginal effects of empagliflozin in patients with type 2 diabetic and refractory angina; A randomized, double-blind placebo-controlled trial (EMPT-angina trial)

Empagliflozin reduces endoplasmic reticulum stress associated TXNIP/NLRP3 activation in tunicamycin-stimulated aortic endothelial cells.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have proven to be of therapeutic significance for cardiovascular diseases beyond the treatment of type 2 diabetes. Recent studies have demonstrated the beneficial effects of SGLT2i on endothelial cell (EC) dysfunction, but the underlying cellular mechanisms remain to be clarified. In this study, we sought to understand the effect of empagliflozin (EMPA; Jardiance®) on cell homeostasis and endoplasmic reticulum (ER) stress signaling. ER stress was induced by tunicamycin (Tm) in human abdominal aortic ECs treated with EMPA over 24 h. Tm-induced ER stress caused increases in the protein expression of thioredoxin interacting protein (TXNIP), NLR-family pyrin domain-containing protein 3 (NLRP3), C/EBP homologous protein (CHOP), and in the ratio of phospho-eIF2α/eIF2α. EMPA (50-100 µM) resulted in a dampened downstream activation of ER stress as seen by the reduced expression of CHOP and TXNIP/NLRP3 in a dose-dependent manner. Nuclear factor erythroid 2-related factor 2 (nrf2) translocation was also attenuated in EMPA-treated ECs. These results suggest that EMPA improves redox signaling under ER stress which in turn attenuates the activation of TXNIP/NLRP3.

THE CARDIOPROTECTIVE EFFECTS OF EMPAGLIFLOZIN IN PATIENTS WITH HEART FAILURE WITH PRESERVED EJECTION FRACTION AND TYPE 2 DIABETES MELLITUS

Introduction. Heart failure with preserved ejection fraction (HFpEF) is a complex clinical syndrome associated with significant morbidity and mortality. Type 2 diabetes mellitus (T2DM) often coexists in patients with HFpEF, further exacerbating the cardiovascular risk. Empagliflozin, a sodium-glucose cotransporter 2 inhibitor, has shown promising results in improving cardiovascular outcomes in patients with T2DM. However, the specific cardioprotective effects of empagliflozin in patients with HFpEF and T2DM remain to be elucidated.
 Aim. To assess the effect of empagliflozin on biochemical markers of heart failure in patients with type 2 diabetes mellitus and heart failure with preserved ejection fraction.
 Materials and Methods. The study included 80 patients with HFpEF and T2DM, with 40 patients in the empagliflozin group and 40 patients in the control group. Baseline characteristics, including age, gender, blood pressure, body mass index, and cardiac markers (HbA1c, NT-proBNP, Galectin-3, and sST2), were assessed. Changes in glycemic control and cardiac markers were analyzed after the treatment period.
 Results. Baseline characteristics showed no significant differences between the two groups, indicating successful randomization. Post-treatment analysis revealed a numerical trend towards improved glycemic control in the empagliflozin group compared to the control group. Notably, empagliflozin treatment led to a significant reduction in NT-proBNP levels, indicating improved cardiac function and reduced cardiac stress. Furthermore, empagliflozin was associated with lower Galectin-3 and sST2 levels, suggesting potential benefits in mitigating cardiac fibrosis, remodeling, and inflammation.
 Conclusions. Empagliflozin treatment in patients with HFpEF and T2DM have multifaceted implications beyond glycemic control. The observed reductions in NT-proBNP, Galectin-3, and sST2 levels suggest potential improvements in cardiac function, fibrosis, remodeling, and inflammatory processes. These findings highlight the potential of empagliflozin as a therapeutic option for managing HFpEF and T2DM, offering the potential for comprehensive cardiovascular benefits in this patient population.

Empagliflozin Reduces Interleukin-6 Levels in Patients with Heart Failure.

Background: The inhibition of sodium-glucose co-transporter 2 (SGLT-2) has been shown to be beneficial in the treatment of diabetic and non-diabetic patients with heart failure. The underlying mechanisms are incompletely understood. The present prospective study investigates for the first time the effect of empagliflozin on various soluble markers of inflammation in patients with reduced ejection fraction (HFrEF). Methods: We included 50 inpatients with HFrEF and diabetes mellitus type 2. A total of 25 patients received a therapy with the SGLT-2-inhibitor empagliflozin in addition to standard medication; the other 25 patients did not receive empagliflozin and were considered the control group. Quality of life, functional status and soluble immunological parameters in serum were assessed at baseline and after 3 months. Results: The baseline characteristics of both groups revealed no significant differences. Patients on empagliflozin demonstrated a significant improvement in the Minnesota living with heart failure questionnaire (baseline 44.2 ± 20.2 vs. 24 ± 17.7; p < 0.001), in distance in the 6-min walk test (baseline 343 ± 145 m vs. 450 ± 115 m; p < 0.001) and in soluble interleukin-6 level (baseline 21.7 ± 21.8 pg/mL vs. 13.7 ± 15.8 pg/mL; p = 0.008). There was no significant change of these or other parameters in the control group (p > 0.05 each). Conclusions: The empagliflozin-induced improvement of quality of life and functional capacity in patients with HFrEF and type 2 diabetes mellitus is accompanied by a substantial reduction of interleukin-6 levels. Thus, anti-inflammatory effects may contribute to the benefits of SGLT-2-inhibitors in heart failure.

Study the effects of empagliflozin on model of chronic depression and interleukin-6 in the brain of male rats

Abstract Background: Empagliflozin (EMP) is an oral anti-diabetic drug with pleiotropic effects such as anti-inflammatory properties. Objectives: To evaluate the antidepressant effect of EMP and describe the link between stress and interleukin-6 (IL-6) level in the brains of male rats. Materials and Methods: In this experiment, 50 rats were separated into five groups G1–G5. The sucrose preference test (SPT) was used to examine the antidepressant effects of fluoxetine and EMP. Rat interleukin enzyme-linked immunosorbent assay kit was used to measure the IL-6 level in rat brain tissue. SPT was performed on each rat on days 0, 10, and 25. Chronic unpredictable stress (CUS) was performed on each rat for 24 days. Results: By the end of day 10, all rats subjected to the CUS program had a substantial (P &lt; 0.05) reduction in sucrose intake index compared to day 0. EMP significantly increases sucrose intake compared to the stressed group. In comparison to the CUS group, fluoxetine significantly increases sucrose intake (P &lt; 0.05). In terms of IL-6, the mean IL-6 level in G2 was considerably greater than in G1. When compared to group 2, the mean IL-6 level was considerably lower in G3 and G5. Conclusions: EMP has antidepressant-like effects and can counteract the impact of stress-increased IL-6 levels in the brains of depressed rats.

Cardioprotective Effects of Sodium Glucose Cotransporter 2 Inhibition in Angiotensin II-Dependent Hypertension Are Mediated by the Local Reduction of Sympathetic Activity and Inflammation.

The cardioprotective effects of sodium glucose cotrasponter 2 (SGLT2) inhibitors seem to be independent from the effects on glycemic control, through little-known mechanisms. In this study, we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be associated with myocardial sympathetic activity and inflammatory cell infiltration in an experimental model of angiotensin II-dependent hypertension. Angiotensin II (Ang II), Ang II plus Empagliflozin, physiological saline, or physiological saline plus empagliflozin were administered to Sprague Dawley rats for two weeks. Blood pressure was measured by plethysmographic method. Myocardial hypertrophy and fibrosis were analysed by histomorphometry, and inflammatory cell infiltration and tyrosine hydroxylase expression, implemented as a marker of sympathetic activity, were evaluated by immunohistochemistry. Ang II increased blood pressure, myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase expression, as compared to the control group. Empagliflozin administration prevented the development of myocardial hypertrophy, fibrosis, inflammatory infiltrates and tyrosine hydroxylase overexpression in Ang II-treated rats, without affecting blood glucose and the Ang II-dependent increase in blood pressure. These data demonstrate that the cardioprotective effects of SGLT2 inhibition in Ang II-dependent hypertension may result from the myocardial reduction of sympathetic activity and inflammation and are independent of the modulation of blood pressure and blood glucose levels.

Repeated administration of adipose-derived mesenchymal stem cells added on beneficial effects of empagliflozin on protecting renal function in diabetic kidney disease rat

BackgroundDiabetic kidney disease (DKD) is one of the most significant public health burdens worldwide. This study explored the renal protections of combined adipose-derived mesenchymal stem cells (ADMSCs) and empagliflozin (EMPA) in DKD rats. MethodsAdult-male-SD rats were equally allocated into group 1 (sham-operated-control), group 2 (DKD), group 3 (DKD + EMPA/20 mg/kg/day since day-14 after CKD-induction), group 4 [DKD + ADMSCs (6.0 × 105/intrarenal-arterial-injection/post-day-28, followed by 1.2 × 106/intravenous injection post-days 35 and 42 after CKD-induction, i.e., defined as repeated administration)] and group 5 (DKD + ADMSCs + EMPA) and kidney was harvested post-day-60 CKD-induction. ResultsThe result showed that the blood sugar and circulatory levels of BUN/creatinine and the ratio of urine protein/creatinine at day 60 were greatly increased in group 2 as compared the SC (i.e., group 1), significantly increased in groups 3 and 4 than in groups 5, but these parameters showed the similar manner in groups 3 and 4, except for blood sugar that was significantly lower in group 3 than in group 4 (all p < 0.0001). The protein levels of inflammation (NF-κB/FNF-α/MMP-9)/oxidative-stress (NOX-1/NOX-2/oxidized protein/p22-phox)/apoptosis (cleaved-caspase-3/cleaved-PARP/mitochondrial-Bax)/fibrosis (TGF-β/Smad 3)/mitochondrial/DNA-damaged (p-DRP1/γ-H2AX) biomarkers revealed a similar manner of creatinine level among the groups (all p < 0.0001). Kidney injury score/fibrotic area/oxidative-stress score (8-OHdG) and cellular levels of kidney-damaged biomarkers (KIM-1/γ-H2AX) showed a unanimous manner. In contrast, the cellular expressions of podocyte components (ZO-1/synaptopodin) revealed an antithetical manner of creatinine among the groups (all p < 0.0001). ConclusionCombined ADMSCs-EMPA was superior to just one therapy for protecting kidney function and ultra-structural integrity in DKD rodents.

Protective effects of empagliflozin on testicular injury induced by torsion/detorsion in adult male rats

Testicular torsion is a known urologic emergency condition and one of the common causes of infertility in males. Hence, prompt diagnosis and treatment play a crucial role in prevention of testicular injury. It has been observed that empagliflozin, a drug for management of hyperglycemia, has anti-oxidative properties against different pathologies, the most important of which are ischemia reperfusion related injuries. This study aims to evaluate the protective effects of empagliflozin on a testicular torsion injury in adolescent rats followed by ischemia/reperfusion (I/R) phenomena. Thirty-six rats were randomly assigned into three groups including sham-operated group received all surgical procedures except testicular torsion-detorsion, torsion/detorsion+dimethyl sulfoxide (DMSO) as vehicle, and torsion/detorsion+empagliflozin (10mg/kg). Testicular torsion was performed for 2h through rotating right testis 720° in the clockwise direction. Thirty minutes before detorsion, a single intraperitoneal dose of empagliflozin was injected to treatment group. Four hours later, orchiectomy was conducted for histopathological and biochemical examinations of testicular tissue specimens. The malondialdehyde (MDA) content in the torsion/detorsion animals was markedly greater than in the animals under sham operated procedure. Moreover, the testicular MDA levels in the torsion/detorsion+empagliflozin group were significantly lower than in the torsion/detorsion group. Also, significant decreases observed in catalase, superoxide dismutase, and glutathione peroxidase activities in the torsion/detorsion group in comparison with sham operated group. These values were significantly improved in the empagliflozin group. Furthermore, histopathological examinations also revealed severe testicular injury which were improved by empagliflozin administration. Empagliflozin prevented increases in oxidative stress markers and subsequently reduced the tissue injury induced by torsion/detorsion in the current study. It can be concluded that administration of empagliflozin before prevents I/R related cellular damage in testicular torsion, possibly via oxidative stress inhibition.

867-P: Empagliflozin-Based Quadruple Therapy vs. Insulin Glargine–Based Therapy in Type 2 Diabetes—Three-Year Follow-up Data

Objectives: To directly compare the long-term effectiveness and durability of sodium glucose co-transporter 2 (SGLT2) inhibitor, an empagliflozin-based quadruple therapy and insulin glargine-based therapy in patients with poorly controlled type 2 diabetes (T2D). Research Design and Methods: Eligibility for this 3-year, open-label, prospective observational study was T2D patients (HbA1c, 7.5 - 12.0%) despite three distinct OADs (metformin, 2000 mg/day; dipeptidyl peptidase-4 inhibitor, maximal dose; and glimepiride ≥6 mg/day) between January 2017 and December 2021. Empagliflozin (25 mg/day, n = 167) or insulin glargine (n = 166) was added as the next agent. Outcomes included the time-to-treatment adjustment, changes in HbA1c level, and safety. Propensity score matched comparison and Kaplan-Meier estimation analysis were used. Results: The estimated median time to treatment adjustment for empagliflozin group was 36.1 months (95% confidential interval [CI], 31.1 - 41.2), which was significantly longer than 18.3 months for the insulin glargine-based therapy (95% CI, 14.5 - 22.0). The mean change in HbA1c from baseline to month 36 were -1.5±1.0% and -1.0±1.4% in the empagliflozin group and the insulin glargine group, respectively (P=0.043). FPG showed a similar trend, although there was no statistical significance (-61.3±54.5 mg/dL vs -4.0±97.5 mg/dL, empagliflozin and insulin glargine group, respectively, P=0.129). Body weight showed a significant decrease in the empagliflozin group (-3.1±3.7 kg, P=0.003), whereas a significant increase in the insulin glargine group (3.2±2.6 kg, P&amp;lt;0.001). Conclusions: This study demonstrated that the effectiveness of empagliflozin as a quadruple combination therapy has been sustained for 3 years. In general, empagliflozin treatment was better than insulin glargine-based combination therapy. Disclosure E.Ku: None. T.Oh: None.

1227-P: Cardiorenal Effectiveness of Empagliflozin vs. GLP-1 Receptor Agonists in Patients with Advanced Chronic Kidney Disease—Results from the EMPRISE Study

Patients with chronic kidney disease (CKD) are at an increased risk of cardiovascular disease, heart failure, and mortality. We reported the final year results of the EMPRISE study program in patients with type 2 diabetes (T2D) and advanced CKD. Using Medicare, Optum, and Marketscan data (2014-19), we identified 10,930 pairs of 1:1 propensity score-matched patients aged &amp;gt;18 years with T2D and CKD stage 3-4 who initiated empagliflozin (EMPA) or a glucagon-like peptide-1 receptor agonist (GLP-1RA). Primary outcomes were hospitalization for heart failure (HHF), a composite of myocardial infarction (MI) or stroke, and end-stage renal disease (ESRD). Secondary outcomes were MI, stroke, and all-cause mortality. We estimated hazard ratios (HR) and rate differences (RD), adjusting for 143 baseline covariates. Compared to GLP-1RA, EMPA was associated with a reduced risk of HHF [HR 0.68 (0.55-0.85); RD -9.44 (-14.78, -4.10)], and ESRD [HR 0.70 (0.56-0.87); RD -9.01 (-14.30, -3.72)], and a trend towards reduced risk for the composite outcome [HR 0.88 (0.72-1.07); RD -3.84 (-9.60, 1.93)]. Estimates for the secondary outcomes were: MI [HR 0.78 (0.61-1.00)], stroke [HR 1.16 (0.83-1.62)], and all-cause mortality [HR 1.08 (0.86-1.36)]. In patients with T2D and advanced CKD in routine care, we observed risk reductions for cardiorenal outcomes with EMPA vs. GLP-1RA. Disclosure P.T.Htoo: Employee; Johnson &amp; Johnson. E.Patorno: Research Support; Boehringer Ingelheim Inc., National Institutes of Health, Patient-Centered Outcomes Research Institute, US Food and Drug Administration. H.Tesfaye: None. D.J.Wexler: Other Relationship; Novo Nordisk A/S. R.Glynn: Research Support; Amarin Corporation, AstraZeneca, Kowa Pharmaceuticals America, Inc., Novartis, Pfizer Inc. N.Schmedt: Employee; Boehringer Ingelheim International GmbH. L.Koeneman: Employee; Eli Lilly and Company, Stock/Shareholder; Eli Lilly and Company. S.Schneeweiss: Consultant; Aetion, Inc., Research Support; UCB, Inc., Boehringer Ingelheim International GmbH, Stock/Shareholder; Aetion, Inc. J.M.Paik: None. Funding Boehringer Ingelheim (116283)

98-LB: Effects of SGLT2 Inhibition on Skeletal Muscle Bioenergetics and Myocellular Lipids in Patients with T2D and HFrEF

Background: The CV benefits of SGLT2i are well established. However, how skeletal muscle (SkM) bioenergetics respond to SGLT2i in T2D and HFrEF remains largely unknown. Objective: To explore the effects of empagliflozin on SkM bioenergetics (phosphorus metabolites &amp; myocellular lipid content) at rest and post-exercise (31P &amp; 1H MRS) and cardiac function (MRI). Methods: Subjects with T2D &amp; HFrEF (&amp;lt;40%) (n=6) were randomized 2:1 to empagliflozin 25mg (SGLT2i) or placebo for 12 wks (Age=59±2.6, BMI=33.3±1.1, A1c=7.1±0.3, EF 28±4%). A cardiac MRI, &amp; static/dynamic 31P &amp; 1H SkM by MRS, were performed before &amp; after treatment. Results: In the empagliflozin group, SkM 31P MRS at rest, showed decrease in phosphodiesterase [PDE]. 31P MRS post-exercise, showed significant improvement in Phosphocreatinine (PCr) recovery, expressed by the K value. 1H MRS showed a reduction of saturated intramyocellular lipids (IMCL-CH2:CH3 ratio). Conclusion: Empagliflozin in subjects with T2D and HFrEF had beneficial effects in SkM energy utilization and muscle recovery post-exercise as determined by a decrease in PDE and increase in K value. Additionally, empagliflozin decreased saturated IMCL, which could be expected to improve mitochondrial function and energy utilization. If similar findings were to occur in cardiac muscle, this could provide a novel mechanism for the beneficial CV effects of SGLT2i. Disclosure Y. Qin: None. N. D. Sanchez: None. A. Moody: None. F. M. Acosta: None. S. Neppala: None. M. Brown: None. H. Honka: None. L. A. Cruz Moreno: None. C. L. Triplitt: Speaker's Bureau; Novo Nordisk. G. D. Clarke: None. E. Cersosimo: None. R. A. DeFronzo: Speaker's Bureau; AstraZeneca. Advisory Panel; AstraZeneca, Bayer Inc., Boehringer-Ingelheim, Novo Nordisk. Research Support; AstraZeneca, Boehringer-Ingelheim, Merck &amp; Co., Inc. C. Solis-Herrera: None. Funding Doris Duke Charitable Foundation; Voelcker Foundation; National Institutes of Health

Serum uric acid lowering and effects of sodium-glucose cotransporter-2 inhibitors on gout: A meta-analysis and meta-regression of randomized controlled trials.

To pool the effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors on gout and to investigate the association of these effects with baseline serum uric acid (SUA), SUA lowering, and underlying conditions, such as type 2 diabetes mellitus (T2DM)/heart failure (HF). PubMed, Embase, Web of Science, Cochrane Library and clinical trial registry websites were searched for randomized controlled trials (RCTs) or post hoc analyses (≥1-year duration; PROSPERO:CRD42023418525). The primary outcome was a composite of gouty arthritis/gout flares and commencement of anti-gout drugs (SUA-lowering drugs/colchicine). Hazard ratios (HRs) with 95% confidence interval (CI) were pooled using a generic inverse-variance method with a random-effects model. Mixed-effects model univariate meta-regression analysis was performed. Five RCTs involving 29 776 patients (T2DM, n = 23 780) and 1052 gout-related events were identified. Compared to placebo, SGLT2 inhibitor use was significantly associated with reduced risk of composite gout outcomes (HR 0.55, 95% CI 0.45-0.67; I2 = 61%, P < 0.001). Treatment benefits did not differ between trials being conducted exclusively in baseline HF versus those conducted in patients with T2DM (P-interaction = 0.37), but were greater with dapagliflozin 10 mg and canagliflozin 100/300 mg (P < 0.01 for subgroup differences). Sensitivity analysis excluding trials that evaluated the effects of empagliflozin 10/25 mg (HR 0.68, 95% CI 0.57-0.81; I2 = 0%) accentuated the benefits of SGLT2 inhibitors with no between-trial heterogeneity (HR 0.46, 95% CI 0.39-0.55; I2 = 0%). Univariate meta-regression found no impact of baseline SUA, SUA lowering on follow-up, diuretic use, or other variables on their anti-gout effects. We found that SGLT2 inhibitors significantly reduced the risk of gout in individuals with T2DM/HF. Lack of an association with SUA-lowering effects suggests that metabolic and anti-inflammatory effects of SGLT2 inhibitors may predominantly mediate their anti-gout benefits.

The Use of Empagliflozin Post Myocardial Infarction.

Empagliflozin is a sodium-glucose cotransporter 2 (SGLT2) inhibitor that is mainly used for the treatment of type 2 diabetes mellitus.The study's objective was to assess empagliflozin's effects and impacts on post-myocardial patients to highlight its worth in comparison to alternative therapies. Only studies evaluating the effects of empagliflozin on individuals who have undergone a myocardial infarction (MI) are included in this review of the literature, which employed PubMed, Google Scholar, and Embase. To compare the advantages of empagliflozin for individuals who have recently experienced a myocardial infarction, abstracts from pertinent articles were retrieved, and complete publications were reviewed. A total of four articles were reviewed, which showed that in patients whosuffered from a recent MI, empagliflozin caused a significant decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP). Additionally, it was shown that these individuals had better echocardiographic results for both structural and functional metrics. With studies showing a significantly larger median NT-proBNP decrease with empagliflozin compared to placebo among patients hospitalised with an acute big MI when empagliflozin was started early and administered in addition to the post-MI care suggested by guidelines, it is safe to say that the benefits outweigh the risks. There are currently larger double-blind trials in progress to prove the hypothesis of the benefits of empagliflozin for post-MI patients.

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

COUNTERPOINT: the Seductive Trap of Relying on Exaggerated Effects in Short-Term Heart Failure Trials to Predict Benefits and Risks in Patients With Long-Term Disease

#4139 EFFECTS OF EMPAGLIFLOZIN ON FLUID OVERLOAD IN CHRONIC KIDNEY DISEASE: AN EMPA-KIDNEY BIOIMPEDANCE SUBSTUDY

Abstract Background and Aims The EMPA-KIDNEY trial showed that, compared to placebo, empagliflozin 10 mg once daily reduced the risk of kidney disease progression or cardiovascular death in 6609 patients with chronic kidney disease at risk of progression. We aimed to assess effects of empagliflozin on bioimpedance-measured fluid overload and adiposity in a subset to better understand the mechanisms of cardiovascular benefits of sodium glucose co-transporter-2 inhibitors. Method This EMPA-KIDNEY substudy added Body Composition Monitor (BCM) measurements at randomization and the 2 and 18 month follow-up visits to the trial's main protocol-specified procedures. The primary outcome was Absolute Fluid Overload (a parameter reflecting overhydration, derived from extracellular and intracellular resistance). Pre-specified subgroup analyses of the primary outcome were by sex, diabetes status, estimated glomerular filtration rate (eGFR) and N-terminal pro-brain-type natriuretic peptide (NT-proBNP) at baseline. The key secondary analysis was a composite of death from heart failure, heart failure hospitalisation or development of new moderate (&amp;gt;7%, ≤15%) or severe (&amp;gt;15%) BCM-measured Relative Fluid Overload. Tertiary outcomes included weight, anthropometry, and other BCM-measurements of body water and adiposity. The primary outcome was analysed used mixed-model repeated measures (MMRM) methods. The key secondary outcome used time-to-first event methods. Results A total of 660 EMPA-KIDNEY participants were recruited into this substudy. Mean age was 64 years, 205 (31%) were female and 245 (37%) had diabetes. Mean (SD) eGFR was 36 (12) ml/min/1.73m2 and median (Q1-Q3) NTpro-BNP was 211 (93-581) ng/L. Mean (SD) Absolute Fluid Overload at baseline was 0.4 (1.6) L, 19% had moderate fluid overload and 5% fulfilled criteria for severe fluid overload at baseline. Compared to placebo, the mean study average absolute difference in Absolute Fluid Overload was -0.24L (95% CI -0.38, -0.11), with similar differences at 2 months and 18 months (Figure 1). This difference was similar in men and women, in people with and without diabetes, and across the spectrum of eGFR and NT-proBNP studied (Figure 2). The number of key secondary outcomes was low and there was no significant difference in the risk of this outcome between treatment groups (35/332 [10%] vs 38/328 [12%], hazard ratio 0.91 [95% CI 0.57, 1.45], p = 0.69). Conclusion In patients with chronic kidney disease, empagliflozin reduced bioimpedance-measured fluid overload irrespective of diabetes status or level of eGFR. This effect persisted for at least 18 months with no evidence of attenuation over time. Funding Boehringer Ingelheim, Eli Lilly and others; Clinicaltrials.gov:NCT03594110.

Combined experimental/computational aspects for the molecular interaction of empagliflozin with bovine serum albumin: Quantification and application to human plasma.

Empagliflozin (EMP) is an oral antihyperglycemic agent for type 2 diabetic patients. The molecular binding of EMP to bovine serum albumin (BSA) was elucidated by a combined experimental/computational approach to fulfil the pharmacokinetics and pharmacodynamics gaps of the cited drug for further development. Fluorescence, synchronous, and three-dimensional fluorescence spectroscopy verified that EMP quenched BSA native fluorescence through a dual static/dynamic mechanism that was further supported by Fӧrster resonance energy transfer and ultraviolet absorption spectroscopy. Fourier transform infrared spectroscopy revealed the conformational variations in BSA secondary structure induced by EMP. Thermodynamic properties of the BSA-EMP complex were also investigated, and the hydrophobic interactions' role in the binding process was demonstrated by the computed enthalpy (ΔH =6.558 kJ mol-1 ) and entropy (ΔS = 69.333 J mol-1 K-1 ). Gibbs free energy (ΔG) values were negative at three distinct temperatures, illuminating the spontaneity of this interaction. In addition, molecular docking studies depicted the optimal fitting of EMP to BSA on Site I (sub-domain IIA) through three hydrogen bonds. Additionally, and based on the quenching effect of EMP on BSA fluorescence, this study suggests a simple validated spectrofluorometric method for the quantitation of the studied drug in bulk form and human plasma samples with reasonable recoveries (96.99-103.10%).

Generalizability of REDUCE-IT eligibility criteria in a large diabetes cardiovascular outcomes trial: A post hoc subgroup analysis of EMPA-REG outcome: Analysis of EMPA-REG OUTCOME using REDUCE-IT criteria

ObjectivesREDUCE-IT showed that icosapent ethyl (IPE) improved cardiovascular (CV) outcomes in participants with established CV disease (CVD) or type 2 diabetes (T2D) and at least one additional risk factor plus mild-moderate hypertriglyceridemia and reasonably controlled low-density lipoprotein cholesterol (LDL-C). As the generalizability of REDUCE-IT has not been investigated in a T2D population with established CVD, this post hoc analysis investigated how many participants from EMPA-REG OUTCOME, which tested the effects of empagliflozin versus placebo on CV outcomes in participants with T2D and CVD, would have been eligible for IPE treatment, and whether CV outcomes differed based on eligibility for IPE treatment. MethodsParticipants from EMPA-REG OUTCOME were screened for inclusion using both REDUCE-IT-like criteria (baseline statin therapy, triglycerides 135–499 mg/dL and LDL-C 41–100 mg/dL) and slightly amended FDA indication criteria (triglycerides ≥150 mg/dL). Analyses were conducted to characterize the study population and CV outcomes in participants eligible for IPE versus those not eligible for IPE. ResultsOf the 7020 participants from EMPA-REG OUTCOME, 1810 (25.8%) fulfilled REDUCE-IT criteria and 3182 (45.3%) fulfilled FDA criteria for IPE treatment. Treatment effects of empagliflozin versus placebo on CV and kidney outcomes and mortality were consistent in participants meeting REDUCE-IT and FDA criteria and those who did not. ConclusionsThese results indicate that a sizable proportion of patients with diabetes and established CVD, such as those in EMPA-REG OUTCOME, may be eligible for IPE treatment to lower residual CV risk. Treatment benefit with empagliflozin was consistent, regardless of REDUCE-IT or FDA eligibility criteria.

MYOCARDIAL REDUCTION OF SYMPATHETIC ACTIVITY IS INVOLVED IN THE ANTIFIBROTIC AND ANTIHYPERTROPHIC EFFECTS OF SGLT2 INHIBITION IN ANGIOTENSIN II-DEPENDENT HYPERTENSION

Objective: The beneficial myocardial effects of SGLT2 inhibitors, a new class of antidiabetic drugs, have been described not only in diabetic patients, but also in heart diseases not associated with diabetes. The positive effects of these drugs go beyond glycemic control and involve multiple mechanisms. In the present study we investigate whether the cardioprotective effects of empagliflozin, a SGLT2 inhibitor, may be dependent on myocardial sympathetic activity in experimental model of angiotensin II-dependent hypertension. Design and method: Experiments were performed in Sprague Dawley rats (n = 26) followed for 4 weeks and divided in the following groups: a) Angiotensin II-treated group (Ang II, 200 ng/kg/min, osmotic minipumps s.c, n = 7); b) Ang II +Empagliflozin-treated group (Empa, 10 mg/kg/day, per os, n = 6); c) control group (physiological saline s.c., n = 7); d) Control+Empagliflozin-treated group (n = 6). Systolic blood pressure was measured by tail cuff method. At the end of the experimental period myocardial interstitial fibrosis (Sirius Red staining) and myocardial hypertrophy were measured by histomorphometric analysis. Myocardial tyrosine hydroxylase expression, used as marker of sympathetic activity, was measured by immunohistochemistry. Results: Ang II caused a significant increase of blood pressure (p&lt;0.0001), myocardial interstitial fibrosis (p&lt;0.01), hypertrophy (p&lt;0.01), and tyrosine hydroxylase expression (p&lt;0.01) as compared to control groups. Empagliflozin treatment did not modify blood glucose in the different groups of rats. Empagliflozin administration did not modify the increase in blood pressure in Ang II treated rats, but prevented the development of myocardial fibrosis, hypertrophy, and tyrosine hydroxylase over-expression. Conclusions: These data demonstrate that in Ang II dependent hypertension Empagliflozin administration prevented the onset of myocardial fibrosis and hypertrophy through the reduction of local sympathetic activity. This effect is independent on the modulation of blood pressure and blood glucose levels.

Comparison of the effects of empagliflozin and sotagliflozin on a zebrafish model of diabetic heart failure with reduced ejection fraction

The sodium-glucose cotransporter 2 (SGLT2) inhibitor empagliflozin (EMPA) and dual SGLT1/2 inhibitor sotagliflozin (SOTA) are emerging as heart failure (HF) medications in addition to having glucose-lowering effects in diabetes mellitus (DM). However, the precise mechanism underlying this cardioprotective effect has not yet been elucidated. Here, we evaluated the effects of EMPA and SOTA in a zebrafish model of DM combined with HF with reduced ejection fraction (DM-HFrEF). To compare the effects of the two drugs, survival, locomotion, and myocardial contractile function were evaluated. The structural binding and modulating effects of the two medications on sodium-hydrogen exchanger 1 (NHE1) were evaluated in silico and in vitro. DM-HFrEF zebrafish showed impaired cardiac contractility and decreased locomotion and survival, all of which were improved by 0.2–5 μM EMPA or SOTA treatment. However, the 25 μM SOTA treatment group had worse survival rates and less locomotion preservation than the EMPA treatment group at the same concentration, and pericardial edema and an uninflated swim bladder were observed. SOTA, EMPA and cariporide (CARI) showed similar structural binding affinities to NHE1 in a molecular docking analysis and drug response affinity target stability assay. In addition, EMPA, SOTA, and CARI effectively reduced intracellular Na+ and Ca2+ changes through the inhibition of NHE1 activity. These findings suggest that both EMPA and SOTA exert cardioprotective effects in the DM-HFrEF zebrafish model by inhibiting NHE1 activity. In addition, despite the similar cardioprotective effects of the two drugs, SOTA may be less effective than EMPA at high concentrations.

Safety and effectiveness of empagliflozin in clinical practice as monotherapy or with other glucose-lowering drugs in Japanese patients with type 2 diabetes: subgroup analysis of a 3-year post-marketing surveillance study

ABSTRACT Background Sodium-glucose co-transporter-2 (SGLT2) inhibitors such as empagliflozin are increasingly prescribed as initial glucose-lowering drugs for type 2 diabetes (T2D), based on their cardiorenal benefits. However, information regarding the safety and the effectiveness of monotherapy with SGLT2 inhibitors in routine clinical practice is limited. Research design and methods We analyzed data from a prospective, 3-year, post-marketing surveillance study of empagliflozin in Japan. We evaluated adverse drug reactions (ADRs) (the primary endpoint) and glycemic effectiveness with or without other glucose-lowering drugs. Results 7931 T2D patients were treated with empagliflozin. At baseline, mean age was 58.7 years, 63.0% were male, and 1835 (23.14%) were not receiving other glucose-lowering drugs. ADRs occurred in 141 (7.68%) and 875 (14.62%) patients initiating empagliflozin as monotherapy or combination therapy, respectively. The most frequent ADRs of special interest with empagliflozin as monotherapy or combination therapy were urinary tract infections (0.82% and 1.14% of patients, respectively) and excessive/frequent urination (0.65%, 1.50%). At last observation, glycated hemoglobin level was reduced by a mean of 0.78% with empagliflozin monotherapy (from baseline mean of 7.55%) and 0.74% with combination therapy (baseline 8.16%). Conclusions Empagliflozin is well tolerated and effective in clinical practice in Japan when initiated as monotherapy or combination therapy.