Sodium-glucose Transporter-2 Inhibitors Research Articles

Missed postoperative metabolic acidosis associated with sodium-glucose transporter 2 inhibitors in cardiac surgery patients: a retrospective analysis

The increasing use of sodium glucose transporter 2 inhibitors (SGLT2i) for treating cardiovascular (CV) diseases and type 2 diabetes (T2D) is accompanied by a rise in euglycemic diabetic ketoacidosis occurrences in cardiac surgery patients. Patients undergoing cardiac surgery, due to their pre-existing CV disease which often requires SGLT2i prescriptions, face an increased risk of postoperative metabolic acidosis (MA) or ketoacidosis (KA) associated with SGLT2i, compounded by fasting and surgical stress. The primary aim of this study is to quantify the incidence of SGLT2i-related postoperative MA or KA and to identify related risk factors. We analyzed data retrospectively of 823 cardiac surgery patients, including 46 treated with SGLT2i from November 2019 to October 2022. Among 46 final cohorts treated preoperatively with SGLT2i, 29 (63%) developed postoperative metabolic complications. Of these 46 patients, stratified into two categories based on postoperative laboratory findings, risk factor analysis were conducted and compared. Analysis indicated a prescription duration over one week significantly elevated the risk of complications (Unadjusted OR, 11.7; p = 0.032*; Adjusted OR, 31.58; p = 0.014*). A subgroup analysis showed that a cardiopulmonary bypass duration of 60 min or less significantly raises the risk of SGLT2i-related postoperative MA in patients with a sufficient prescription duration. We omitted the term "diabetes" in describing complications related to SGLT2i, as these issues are not exclusive to T2D patients. Awareness of SGLT2i-related postoperative MA or KA can help clinicians distinguish between non-life-threatening conditions and severe causes, thereby preventing unnecessary tests and ensuring best practice.

Hepatoprotective and cardioprotective effects of empagliflozin in spontaneously hypertensive rats fed a high-fat diet

A combination of liver and heart dysfunction worsens the prognosis of human survival. The aim of this study was to investigate whether empagliflozin (a sodium-glucose transporter-2 inhibitor) has beneficial effects not only on cardiac and renal function but also on hepatic function. Adult (6-month-old) male spontaneously hypertensive rats (SHR) were fed a high-fat diet (60% fat) for four months to induce hepatic steatosis and mild heart failure. For the last two months, the rats were treated with empagliflozin (empa, 10 mg.kg-1.day-1 in the drinking water). Renal function and oral glucose tolerance test were analyzed in control (n=8), high-fat diet (SHR+HF, n=10), and empagliflozin-treated (SHR+HF+empa, n=9) SHR throughout the study. Metabolic parameters and echocardiography were evaluated at the end of the experiment. High-fat diet feeding increased body weight and visceral adiposity, liver triglyceride and cholesterol concentrations, and worsened glucose tolerance. Although the high-fat diet did not affect renal function, it significantly worsened cardiac function in a subset of SHR rats. Empagliflozin reduced body weight gain but not visceral fat deposition. It also improved glucose sensitivity and several metabolic parameters (plasma insulin, uric acid, and HDL cholesterol). In the liver, empagliflozin reduced ectopic lipid accumulation, lipoperoxidation, inflammation and pro-inflammatory HETEs, while increasing anti-inflammatory EETs. In addition, empagliflozin improved cardiac function (systolic, diastolic and pumping) independent of blood pressure. The results of our study suggest that hepatoprotection plays a decisive role in the beneficial effects of empagliflozin in preventing the progression of cardiac dysfunction induced by high-fat diet feeding.

Association of anti-diabetic drugs and COVID-19 outcomes in patients with diabetes mellitus type 2 and cardiomyopathy

There is a scarcity of information on the population with diabetes mellitus type 2 and cardiomyopathy (PDMC) in COVID-19, especially on the association between anti-diabetic medications and COVID-19 outcomes. Study is designed as a retrospective cohort analysis covering 2020 and 2021. Data from National Diabetes Registry (CroDiab) were linked to hospital data, primary healthcare data, the SARS-CoV-2 vaccination database, and the SARS-CoV-2 test results database. Study outcomes were cumulative incidence of SARS-CoV-2 positivity, COVID-19 hospitalizations, and COVID-19 deaths. For outcome predictors, logistic regression models were developed. Of 231 796 patients with diabetes mellitus type 2 in the database, 14 485 patients had cardiomyopathy. The two2-year cumulative incidence of all three studies' COVID-19 outcomes was higher in PDMC than in the general diabetes population (positivity 15.3% vs. 14.6%, p = 0.01; hospitalization 7.8% vs. 4.4%, p < 0.001; death 2.6% vs. 1.2%, p < 0.001). Sodium-Glucose Transporter 2 (SGLT-2) inhibitors therapy was found to be protective of SARS-CoV-2 infections [OR 0.722 (95% CI 0.610–0.856)] and COVID-19 hospitalizations [OR 0.555 (95% CI 0.418–0.737)], sulfonylureas to be risk factors for hospitalization [OR 1.184 (95% CI 1.029–1.362)] and insulin to be a risk factor for hospitalization [OR 1.261 (95% CI 1.046–1.520)] and death [OR 1.431 (95% CI 1.080–1.897)]. PDMC are at greater risk of acquiring SARS-CoV-2 infection and having worse outcomes than the general diabetic population. SGLT-2 inhibitors therapy was a protective factor against SARS-CoV-2 infection and against COVID-19 hospitalization, sulfonylurea was the COVID-19 hospitalization risk factor, while insulin was a risk factor for all outcomes. Further research is needed in this diabetes sub-population.

Acute kidney injury events in patients with diabetes using sodium glucose transporter 2 inhibitors: a meta-analysis of cohort studies.

To conduct a meta-analysis of cohort studies to explore the association between acute kidney injury (AKI) and the effect of sodium glucose transporter 2inhibitors (SGLT2 inhibitors) in patients with type 2 diabetes mellitus (T2DM). PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were comprehensively searched for eligible studies until April 4, 2023 on the association between AKI and use of SGLT2 inhibitors in T2DM patients. Odds ratios (ORs) and their 95% confidence intervals (CIs) were pooled using the Mantel-Haenszel method. A total of 10 cohort studies (20 cohorts) and 526,863 participants were included in the meta-analysis. Compared with other glucose-lowering drugs (oGLDs), SGLT2 inhibitors were associated with a decreased risk of AKI (OR = 0.50, 95% CI 0.38-0.66, I2 = 96%). Meanwhile, SGLT2 inhibitors demonstrated a significant reduction in the incidence of AKI hospitalization compared with oGLDs (OR = 0.54, 95% CI 0.43-0.68, I2 = 92.0%). The result was consistent across different subgroups, and was robust to sensitivity analysis. Compared with oGLDs, SGLT2 inhibitors reduced the risk of suffering AKI and AKI hospitalization in the real-world setting. Vigilance to the occurrence of AKI should not be an obstacle to discourage clinicians from prescribing SGLT2 inhibitors.

The safety of sodium glucose transporter 2 inhibitors and trends in clinical and hemodynamic parameters in patients with left ventricular assist devices.

The safety and impact of sodium glucose transporter 2 inhibitors (SGLT2-I) in patients with left ventricular assist devices (LVAD) are unknown. A retrospective analysis of all consecutive patients who underwent LVAD Heart Mate 3 (HM3) implantation at a single medical center and received SGLT2-I therapy following surgery was conducted. LVAD parameters, medical therapy, laboratory tests, echocardiography, and right heart catheterization (RHC) study results were recorded and compared before and after initiation of SGLT2-I. SGLT2-I medications were initiated in 29 (21%) of 138 patients following HM3 implantation (23 (79%) received Empagliflozin and 6 (21%) Dapagliflozin). The mean age at the time of LVAD implantation was 62 ± 6.7 years, 25 (86%) were male, and 23 (79%) had diabetes mellitus. The median time from HM3 implantation to SGLT2-I initiation was 108 days, IQR (26-477). Following SGLT2-I therapy, the daily dose of furosemide decreased from 47 to 23.5 mg/day (mean difference = 23.5 mg/d, 95% CI 8.2-38.7, p = 0.004) and significant weight reduction was observed (mean difference 2.5 kg, 95% CI 0.7-4.3, p = 0.008). Moreover, a significant 5.6 mm Hg reduction in systolic pulmonary artery pressure (sPAP) was measured during RHC (95% CI 0.23-11, p = 0.042) in a subgroup of 11 (38%) patients. LVAD parameters were similar before and after SGLT2-I initiation (p > 0.2 for all). No adverse events were recorded during median follow-up of 354 days, IQR (206-786). SGLT2-I treatment is safe in LVAD patients and might contribute to reduction in patients sPAP.

Risk of Dementia in Patients with Diabetes Using Sodium-Glucose Transporter2 Inhibitors (SGLT2i): A Systematic Review, Meta-Analysis, and Meta-Regression.

Dementia is quite prevalent and among the leading causes of death worldwide. According to earlier research, diabetes may increase the possibility of developing dementia. However, the association between antidiabetic agents and dementia is not yet clear. This investigation examines the association between the use of sodium-glucose transporter2 inhibitors (SGLT2i) and the risk of dementia in patients with diabetes. Up to April 18, 2023, four databases-Europe PMC, Medline, Scopus, and Cochrane Library-were searched for relevant literature. We included all studies that examine dementia risk in adults with diabetes who use SGLT2i. Random-effect models were used to compute the outcomes in this investigation, producing pooled odds ratios (OR) with 95% confidence intervals (CI). Pooled data from seven observational studies revealed that SGLT2i use was linked to a lower risk of dementia in people with diabetes (OR 0.45, 95%CI 0.34-0.61; p < 0.00001, I2 = 97%). The reduction in the risk of dementia due to SGLT2i's neuroprotective effect was only significantly affected by dyslipidemia (p = 0.0004), but not by sample size (p = 0.2954), study duration (p = 0.0908), age (p = 0.0805), sex (p = 0.5058), hypertension (p = 0.0609), cardiovascular disease (p = 0.1619), or stroke (p = 0.2734). According to this research, taking SGLT2i reduces the incidence of dementia in people with diabetes by having a beneficial neuroprotective impact. Randomized controlled trials (RCTs) are still required in order to verify the findings of our research.

Investigating the association between the administration of SGLT-2 inhibitors and the risk of urinary tract infection; a systematic review and meta-analysis

Introduction: Sodium-glucose transporter 2 (SGLT-2) inhibitors induce glycosuria. Therefore, using a meta-analysis study, this study aimed to evaluate the correlation between SGLT2 inhibitor administration and urinary tract infection (UTI) risk. Materials and Methods: In this systematic review and meta-analysis, we conducted searches on Scopus, PubMed, Web of Science, Cochrane, and Google Scholar without time limitations up to October 16, 2023. Data were analyzed using STATA 14 software, and a significance level of P &lt; 0.05 was considered. Results: The combination of 11 studies revealed that the use of SGLT2 inhibitors, when compared to glucagon-like peptide-1 (GLP-1) receptor agonists, reduced the risk of UTI (OR = 0.77; 95% CI: 0.62, 0.95) and when compared to insulin (OR = 0.74; 95% CI: 0.63, 0.87). However, the administration of SGLT2 inhibitors, when compared to dipeptidyl peptidase‐4 (DPP‐4) inhibitors (OR = 1.09; 95% CI: 0.90, 1.32), sulfonylureas (OR = 1.35; 95% CI: 0.88, 2.05), biguanide initiators (OR = 1.14; 95% CI: 1.05, 1.24), thiazolidinediones (OR = 1.19; 95% CI: 0.58, 2.44), and other antidiabetic drugs (OR = 1.20; 95% CI: 0.92, 1.57), did not increase the risk of UTI. The administration of dapagliflozin (OR = 1.51; 95% CI: 0.60, 3.81), canagliflozin (OR = 1.22; 95% CI: 0.47, 3.15), and empagliflozin (OR = 3.22; 95% CI: 2.97, 3.48) showed associations with UTI risk. Furthermore, the correlation between SGLT2 inhibitors use and UTI risk was observed in cohort studies (OR = 1.14; 95% CI: 0.98, 1.32), cross-sectional studies (OR = 0.86; 95% CI: 0.64, 1.14), in males (OR = 1; 95% CI: 0.72, 1.40), and females (OR = 1.17; 95% CI: 0.91, 1.52). Conclusion: Empagliflozin, in contrast to dapagliflozin and canagliflozin, increases the risk of UTI. Registration: This study has been compiled based on the PRISMA checklist, and its protocol was registered on the PROSPERO (CRD42023479548) and Research Registry (UIN: reviewregistry1742) Websites

Absolute treatment effects of novel antidiabetic drugs on a composite renal outcome: meta-analysis of digitalized individual patient data

BackgroundAbsolute treatment benefits—expressed as numbers needed to treat—of the glucose lowering and cardiovascular drugs, glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose transporter 2 (SGLT2) inhibitors on renal outcomes remain uncertain. With the present meta-analysis of digitalized individual patient data, we aimed to display and compare numbers needed to treat of both drugs on a composite renal outcome.MethodsFrom Kaplan–Meier plots of major cardiovascular outcome trials of GLP-1 receptor agonists and SGLT2 inhibitors vs. placebo, we digitalized individual patient time-to-event information on composite renal outcomes with WebPlotDigitizer 4.2; numbers needed to treat from individual cardiovascular outcome trials were estimated using parametric Weibull regression models and compared to original data. Random-effects meta-analysis generated meta-numbers needed to treat with 95% confidence intervals (CI).ResultsTwelve cardiovascular outcome trials (three for GLP-1 receptor agonists, nine for SGLT2 inhibitors) comprising 90,865 participants were included. Eight trials were conducted in primary type 2 diabetes populations, two in a primary heart failure and two in a primary chronic kidney disease population. Mean estimated glomerular filtration rate at baseline ranged between 37.3 and 85.3 ml/min/1.73 m2. Meta-analyses estimated meta-numbers needed to treat of 85 (95% CI 60; 145) for GLP-1 receptor agonists and 104 (95% CI 81; 147) for SGLT2 inhibitors for the composite renal outcome at the overall median follow-up time of 36 months.ConclusionThe present meta-analysis of digitalized individual patient data revealed moderate and similar absolute treatment benefits of GLP-1 receptor agonists and SGLT2 inhibitors compared to placebo for a composite renal outcome.Graphical

[ImmunoglobulinA vasculitis].

The immune-mediated small vessel vasculitis is known as Schoenlein-Henoch purpura predominantly from pediatrics and in these cases occurs more frequently after infections of the upper airways. In adults, immunoglobulinA (IgA) vasculitis often proceeds more severely und recurrently with the classical tetrad of skin manifestations in the sense of leukocytoclastic vasculitis, joint affection, gastrointestinal involvement and IgA nephritis, in contrast to the mostly mild and self-limiting course in children. The background of this systemic vasculitis with formation of IgA immune complexes is considered to be an altered glycosylation of IgA, as this causes the exposure of binding sites for autoantibodies so that an immune complex reaction can be elicited. This ultimately leads to perivascular deposition of IgA and afurther activation of neutrophils. Groundbreaking in the diagnostics is the histological detection of leukocytoclastic vasculitis and in cases of renal manifestations akidney biopsy with characteristic deposits of immune complexes, which cannot be clearly differentiated from IgA nephropathy. The treatment is aimed at the respective manifestation and is mostly based on consensus recommendations due to the lack of randomized studies. In addition to immunosuppressive medication, in the presence of achronic kidney disease general nephroprotection is becoming increasingly more important also by inhibition of sodium-glucose transporter2 (SGLT2). The type and extent of kidney involvement and also rare cardiac manifestations are the main determinants of the prognosis. Continuous medical accompaniment of those affected is necessary due to the possible progression of the disease and the risk of recurrence.

Sodium-Glucose Transporter 2 (SGLT2) Inhibitors and Iron Deficiency in Heart Failure and Chronic Kidney Disease: A Literature Review.

Heart failure (HF) and chronic kidney disease (CKD) are associated with high mortality. In both disorders, impaired iron homeostasis, mostly in the form of a functional iron deficiency, is a frequent co-morbidity. In HF, functional iron deficiency and management by i.v. iron supplementation have been proven to affect both prognosis and functional capacity. In the same context, iron supplementation is routine for the adequate management of renal anemia in CKD. In numerous recent studies in HF and in CKD, sodium-glucose transporter 2 (SGLT2) inhibitor treatment has been proven to significantly reduce mortality. Furthermore, the same trials showed that these drugs alleviate iron deficiency and anemia. These effects of SGLT2 inhibitors may be due to an amelioration of inflammation with reduced interleukin-6 (IL-6) and to an enhancement of autophagy with increased sirtuin 1 (SIRT1), both associated with modified production of hepcidin and enhanced ferritinophagy. However, the exact pathogenic basis of the beneficial SGLT2 inhibitor action is not fully elucidated. Nevertheless, effects on iron homeostasis might be a potential explanatory mechanism for the powerful SGLT2 inhibitors' cardiovascular and renal outcome benefits. In addition, the interaction between iron supplementation and SGLT2 inhibitors and its potential impact on prognosis remains to be clarified by future studies. This review represents a significant effort to explore the complex relationships involved, seeking to elucidate the intricate mechanisms by which SGLT2 inhibitors influence iron homeostasis.

The changes of cardiac energy metabolism with sodium-glucose transporter 2 inhibitor therapy.

To investigate the specific effects of s odium-glucose transporter 2 inhibitor (SGLT2i) on cardiac energy metabolism. A systematic literature search was conducted in eight databases. The retrieved studies were screened according to the inclusion and exclusion criteria, and relevant information was extracted according to the purpose of the study. Two researchers independently screened the studies, extracted information, and assessed article quality. The results of the 34 included studies (including 10 clinical and 24 animal studies) showed that SGLT2i inhibited cardiac glucose uptake and glycolysis, but promoted fatty acid (FA) metabolism in most disease states. SGLT2i upregulated ketone metabolism, improved the structure and functions of myocardial mitochondria, alleviated oxidative stress of cardiomyocytes in all literatures. SGLT2i increased cardiac glucose oxidation in diabetes mellitus (DM) and cardiac FA metabolism in heart failure (HF). However, the regulatory effects of SGLT2i on cardiac FA metabolism in DM and cardiac glucose oxidation in HF varied with disease types, stages, and intervention duration of SGLT2i. SGLT2i improved the efficiency of cardiac energy production by regulating FA, glucose and ketone metabolism, improving mitochondria structure and functions, and decreasing oxidative stress of cardiomyocytes under pathological conditions. Thus, SGLT2i is deemed to exert a benign regulatory effect on cardiac metabolic disorders in various diseases. https://www.crd.york.ac.uk/, PROSPERO (CRD42023484295).

Effects of 3-month dapagliflozin on left atrial function in treatment-naïve patients with type 2 diabetes mellitus: assessment using 4-dimensional echocardiography

BackgroundThe sodium-glucose transporter-2 (SGLT-2) inhibitor dapagliflozin can improve left ventricular (LV) performance in patients with type 2 diabetes mellitus (T2DM). However, the effects on left atrial (LA) function in treatment-naïve T2DM patients remain unclear. The aim of our study was 1) to investigate the effects of 3-month treatment with dapagliflozin on LA function in treatment-naïve patients with T2DM using 4-dimensional automated LA quantification (4D Auto LAQ) and 2) to explore linked covariation patterns of changes in clinical and LA echocardiographic variables. Methods4D Auto LAQ was used to evaluate LA volumes, longitudinal and circumferential strains in treatment-naïve T2DM patients at baseline, at follow-up, and in healthy control (HC). Sparse canonical correlation analysis (sCCA) was performed to capture the linked covariation patterns between changes in clinical and LA echocardiographic variables within the treatment-naïve T2DM patient group. ResultsThis study finally included 61 treatment-naïve patients with T2DM without cardiovascular disease and 39 healthy controls (HC). Treatment-naïve T2DM patients showed reduced LA reservoir and conduit function at baseline compared to HC, independent of age, sex, BMI and blood pressure (LASr: 21.11 ± 5.39 vs. 27.08 ± 5.31 %, padjusted = 0.017; LAScd: -11.51 ± 4.48 vs. -16.74 ± 4.51 %, padjusted = 0.013). After 3-month treatment with dapagliflozin, T2DM patients had significant improvements in LA reservoir and conduit function independent of BMI and blood pressure changes (LASr: 21.11 ± 5.39 vs. 23.84 ± 5.74 %, padjusted < 0.001; LAScd: -11.51 ± 4.48 vs. -12.75 ± 4.70 %, padjusted < 0.001). The clinical and LA echocardiographic parameters showed significant covariation (r = 0.562, p = 0.039). In the clinical dataset, changes in heart rate, insulin, and BMI were most associated with the LA echocardiographic variate. In the LA echocardiographic dataset, changes in LAScd, LASr, and LASr_c were most associated with the clinical variate. ConclusionCompared with HC, treatment-naïve patients with T2DM had lower LA function, and these patients benefited from dapagliflozin administration, particularly in LA function.

[Heart failure: update of the ESC 2023 guidelines].

The 2023 update of the European Society of Cardiology (ESC) guidelines recommends (classIA) the administration of sodium-glucose transporter 2inhibitors (SGLT2i) also for patients with heart failure with preserved ejection fraction (HFpEF) and mildly reduced EF (HFmrEF). Thus, SGLT2i are the only medication that should be given to all heart failure patients for improvement of prognosis independent of left ventricular EF. The rapid administration of the fantastic four drugs and their prompt titration after aheart failure decompensation is now included in the guidelines with a class IB recommendation. For patients with reduced EF (HFrEF) or HFmrEF and iron deficiency there is now a class IIa recommendation for intravenous administration of ferric carboxymaltose or ferric derisomaltose.

Impact of the role of cardiology pharmacy specialist on the improvement of quality indicators among patients with heart failure and reduced ejection fraction

Abstract Background 2021 European Society of Cardiology quality indicators (QIs) for the care and outcomes of adults contains a domain for patients with heart failure with reduced ejection fraction (HFrEF) for initial treatment of guideline-directed medical therapy (GDMT) which includes beta-blocker (BB), angiotensin-converting enzyme inhibitor (ACEI) or angiotensin-neprilysin receptors inhibitors (ARNI), mineralocorticoid receptor antagonist (MRA), and sodium-glucose transporter-2 inhibitor (SGLT2i). The QIs for the individual GDMT is estimated by finding the proportion of patients with HFrEF who are prescribed each therapy in the absence of any contraindication. Purpose To identify the role of the board certified cardiology pharmacist (BCCP) on improving the quality indicators regarding the prescribing of GDMT among patients with HFrEF during hospitalization and before discharge. Methods A cross-sectional study was conducted at the cardiac care unit in a single heart center in Iraq between January 2021 to February 2023. Among the multidisciplinary team member at this unit is a BCCP who suggests optimization of medical therapy based on the recommendations of updated European or American guidelines for the management of different cardiovascular diseases including HFrEF. The suggestion then discussed with the cardiologists for agreement. The study included the medical records for patients with HFrEF and BCCP interventions whether the interventions regarding GDMT or other medical therapy interventions. Data were reviewed and were analyzed to identify the specific interventions related to the initiation of one or more GDMT in each patients. Results Among 164 patients with HFrEF with BCCP interventions, there were 102 (62%) patients who were eligible for one or more of the GDMTs prescription which was suggested by BCCP. The most GDMT initiated was MRA 53 (43%) among 123 interventions and in 53 (52%) of 102 patients (Figure 1). QIs were improved (100%) for BB, ACEI/ARNI, MRA, and SGLT2i among eligible patients as shown in table 1. Conclusions The role of BCCP is essential among heart team for improving QIs related to the GDMT prescription among patients with HFrEF based on the recommendations of the updated guidelines. BCCP mainly improved the QIs for the prescription of MRA.Frequency of GDMT Initiation by BCCPGDMT Initiation Reflecting Improved QIs

Empagliflozin improves diastolic function in obese ZSF1 rats by restoring the cardiac mitochondrial respiratory capacity

Abstract Background Clinical studies demonstrated beneficial effects of Sodium-Glucose-Transporter 2 inhibitors (SGLT2i) on the combined risk of cardiovascular death or heart failure hospitalization in patients with heart failure with preserved ejection fraction (HFpEF). However, underlying processes leading to cardioprotection remain unclear. Purpose The present study aimed to elucidate the impact of Empagliflozin on myocardial function and metabolism in a rat model (ZSF1 rat) with established HFpEF and to analyze underlying mechanisms. Methods 24 week old, obese ZSF1 rats were randomized either receiving standard care (obese) or Empagliflozin (Empa, 30 mg/kg/d p.o.). ZSF1 lean rats (lean) served as healthy controls. All animals underwent a baseline, intermediate and final echocardiography. After 8 weeks of treatment, hemodynamics were measured invasively, blood samples were taken, cardiac mitochondrial function was assessed and left ventricular tissue was collected for molecular and histological analyses or for transmission electron microscopy (TEM). Results Compared to the obese control Empa treated obese rats demonstrated a significantly improved diastolic function already at 4 weeks of treatment (E/é: lean: 17.9 ± 0.8; obese: 23.7 ± 0.7, p&amp;lt;0.001 vs. lean; Empa: 21.0 ± 1.1, p&amp;lt;0.05 vs. lean; p&amp;lt;0.05 vs. obese), which reached the level of healthy controls after 8 weeks of treatment (E/é: lean: 17.5 ± 0.7; obese: 24.4 ± 1.1, p&amp;lt;0.001 vs. lean; Empa: 19.4 ± 0.8, p&amp;lt;0.001 vs. obese). This was accompanied by reduced hypertrophy, fibrosis, left ventricular stiffness and inflammation as well as by improved hemodynamics. Except for a slightly improved myocardial ketone body utilization in Empa treated rats, there was no shift in metabolic substrate preference between groups. Cardiac mitochondrial respiratory function observed in untreated obese rats was significantly impaired compared to healthy controls but restored by Empa treatment (Vmax of complex II: lean: 0.15 ± 0.007 nmol O2/s/mg, obese: 0.12 ± 0.004 nmol O2/s/mg, p&amp;lt;0.01 vs. lean; Empa: 0.17 ± 0.006 nmol O2/s/mg, p&amp;lt;0.05 vs. lean, p&amp;lt;0.001 vs. obese). Moreover, mitochondrial respiratory capacity correlated with diastolic function, suggesting a pivotal role of restored respiratory function for improved diastolic relaxation. TEM revealed reduced size of cardiac mitochondria in obese rats, which was significantly restored by Empa. Proteomic analysis demonstrated major changes in proteins involved in mitochondrial oxidative phosphorylation and antioxidant metabolism. Conclusions The present study demonstrates for the first time beneficial effects of Empaglifozin on cardiac remodeling, diastolic function and hemodynamics in an obese rat model of HFpEF. These effects were accompanied by improved mitochondrial respiratory function, enhanced ketone body utilization and improved antioxidant capacity.

Abstract 11978: Invasive Hemodynamic Changes Associated With Sodium Glucose Transporter-2 Inhibitors: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Introduction: Sodium-Glucose cotransporter-2 inhibitors (SGLT2i) have been shown to lower incident heart failure (HF) and HF hospitalizations, but the mechanism of benefits in relation to invasive hemodynamics remain unclear. This meta-analysis explores the central hemodynamic effects of SGLT2i. Methods: Using PRISMA guidelines, we systematically reviewed PubMed, Embase, CINAHL, Cochrane library, Ovid MEDLINE, and Google scholar from inception to April 2023 for randomized trials evaluating the effect of SGLT2i on central hemodynamics. Included patients were on guideline directed medical therapy and SGLT2i was added in the experimental group compared to placebo for 3-6 months. Rest and peak-exercise central hemodynamics was measured via right heart catheterization pre- and post-intervention. Random-effect model meta-analysis at 95% confidence interval (CI) was done using RevMan 5.4. Results: Out of 267 articles identified, 3 studies with a total of 145 patients were included in the meta-analysis. The mean age was 62.8 + 4.0 years, 70.0% were male and mean BMI was 31.9 + 2.2. Compared to placebo, SGLT2i were associated with reduction in weighted mean difference of pulmonary capillary wedge pressure (PCWP) by 2.71 (95% CI: -4.33 to -1.08, I 2 =2%, p = 0.001) and 4.17 (95% CI: -7.20 to -1.13, I 2 =0%, p = 0.007) mmHg at rest and peak exercise respectively. Similarly, SGLT2i reduced mean pulmonary artery pressure (mPAP) by 1.16 (95% CI: -3.00 to 0.69, I 2 =0%, p = 0.22) and 2.73 (95% CI: -5.63 to 0.18, I 2 =20%, p = 0.07) mmHg at rest and peak exercise respectively, however this was not statistically significant. Conclusions: SGLT2i significantly reduced PCWP at rest and peak exercise. Rest and peak exercise mPAP were also reduced compared to baseline but not statistically significant. This hypothesis-generating study offers mechanistic insights into the association of favorable hemodynamic effects underpinning to the HF benefits of SGLT2i.

Predictors of efficacy of Sodium-GLucose Transporter-2 inhibitors and Glucagon-Like Peptide 1 receptor agonists: Aretrospective cohort study.

The aim of the present study was to verify predictors of HbA1c reduction with Sodium-GLucose Transporter-2 (SGLT2) inhibitors and Glucagon-Like Peptide 1 (GLP1) receptor agonists in routine clinical practice. A retrospective cohort study was performed, enrolling patients with type 2 diabetes aged ≥18years who received a prescription of an SGLT2 inhibitor or a long-acting GLP1 receptor agonist with at least 6months of persistence in therapy. Therapeutic success was defined as HbA1c reduction >10mmol/mol or attainment of the recommended HbA1c target. Out of 236 patients receiving SGLT2 inhibitors, 148 were categorised as successes: successes had a mean lower age and higher estimated Glomerular Filtration Rate than failures, but only age retained statistical significance at multivariate analysis (Odds Ratio with 95% confidence interval: 0.94 [0.91-0.98], p=0.006). In the GLP1 receptor agonists cohort (N=214) there were 146 successes, showing a significantly shorter duration of diabetes even after adjusting for age, and baseline HbA1c (HR 0.96 [0.91-0.99], p=0.02). The present study is a preliminary exploration of factors associated with HbA1c response to SGLT2 inhibitors and GLP1 receptor agonists. Differences in predictors of HbA1c changes across different classes of drugs could be useful in identifying the most suitable drug in individual patients. SGLT2 inhibitors seem to be associated with a greater reduction of HbA1c in younger subjects, and GLP1 agonists in those with a shorter duration of diabetes.

Effect of SGLT2 inhibitors on fractures, BMD, and bone metabolism markers in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

This meta-analysis aims to evaluate the impact of Sodium Glucose Transporter 2 (SGLT2) inhibitors on fractures, bone mineral density (BMD), and bone metabolism markers in type 2 diabetes mellitus (T2DM) patients.Pooled relative risk (RR) with 95% confidence interval (CI) assessed the relationship between SGLT2 inhibitors and fracture risk. Weighted mean difference (WMD) with 95% CI explored the correlation between SGLT2 inhibitors and BMD, as well as bone metabolism markers.A total of 20 randomised controlled trials (RCTs) involving 12,764 patients were analysed. No significant association emerged between SGLT2 inhibitor use and elevated fracture risk (pooled RR = 1.21, 95% CI [0.95, 1.54], I2 = 22%). Furthermore, SGLT2 inhibitors exhibited no substantial effects on BMD changes at the lumbar spine (WMD = -0.02, 95% CI [-0.38, 0.34]), femoral neck (WMD = 0.11, 95% CI [-0.28, 0.50]), total hip (WMD = -0.20, 95% CI [-0.41, 0.01]), and distal forearm (WMD = -0.20, 95% CI [-0.62, 0.22]). Similarly, no notable impact of SGLT2 inhibitors on bone metabolism markers, including CTX (WMD = 0.04, 95% CI [-0.02, 0.09]), P1NP (WMD = 1.06, 95% CI [-0.44, 2.57]), PTH (WMD = 0.34, 95% CI [-0.07, 0.75]), calcium (WMD = 0.01, 95% CI [-0.02, 0.04]), and phosphate (WMD = 2.37, 95% CI [-0.76, 5.49]).The findings suggest that the utilization of SGLT2 inhibitors is not significantly linked to an elevated risk of fractures in individuals with T2DM. However, further clinical investigations and extended follow-up periods are warranted to establish more conclusive determinations.

Sodium Glucose Transporter-2 Inhibitors (SGLT2Is)-TLRs Axis Modulates Diabetes.

Diabetes affects millions of people worldwide and is mainly associated with impaired insulin function. To date, various oral anti-diabetic drugs have been developed, of which, the sodium glucose transporter-2 inhibitors (SGLT2Is) are of the most recent classes that have been introduced. They differ from other classes in terms of their novel mechanism of actions and unique beneficial effects rather than just lowering glucose levels. SGLT2Is can protect body against cardiovascular events and kidney diseases even in non-diabetic individuals. SGLT2Is participate in immune cell activation, oxidative stress reduction, and inflammation mediation, thereby, moderating diabetic complications. In addition, toll like receptors (TLRs) are the intermediators of the immune system and inflammatory process, thus it's believed to play crucial roles in diabetic complications, particularly the ones that are related to inflammatory reactions. SGLT2Is are also effective against diabetic complications via their anti-inflammatory and oxidative properties. Given the anti-inflammatory properties of TLRs and SGLT2Is, this review investigates how SGLT2Is can affect the TLR pathway, and whether this could be favorable toward diabetes.

Dose-dependent relationship between SGLT2 inhibitor hold time and risk for postoperative anion gap acidosis: a single-centre retrospective analysis

BackgroundUse of sodium-glucose transporter-2 (SGLT2) inhibitors has dramatically increased over the past decade. This medication class predisposes patients to euglycaemic diabetic ketoacidosis, particularly during times of physiologic stress, including fasting and surgery. Beyond case reports and series, a systematic description of perioperative metabolic effects of SGLT2 inhibitors is lacking. MethodsWe examined the degree of anion gap acidosis, controlling for non-ketone anions, in patients undergoing surgery at Massachusetts General Hospital in 2016–22. We constructed a multivariable regression model incorporating known non-ketone contributors to the postoperative anion gap (albumin, lactate, estimated glomerular filtration rate, and preoperative anion gap), hold time, and interaction terms between hold time and three previously suggested risk factors for euglycaemic diabetic ketoacidosis: emergency surgery, cardiac surgery, and insulin use. ResultsIn 463 patients on SGLT2 inhibitors, we observed a strong association between decreased hold time and postoperative anion gap (P<0.001 in a univariable analysis; −0.43, 95% confidence interval [−0.76 to −0.11] change in anion gap per day held, P=0.01 in a multivariable analysis). A significant interaction between hold time and emergency surgery was observed, whereas there was no apparent interaction with insulin use or cardiac surgery. ConclusionsThese findings provide the first evidence that an anion gap acidosis, likely from ketoacids, develops in all patients who do not hold SGLT2 inhibitors before surgery rather than in an idiosyncratic few. If an SGLT2 inhibitor is unable to be stopped, postoperative monitoring of anion gap and serum ketones can help detect clinically significant euglycaemic diabetic ketoacidosis, particularly in those undergoing emergency surgery.