SGLT2 Inhibitors Research Articles

Abstract 4138420: Impact of the American Heart Association Get-With-The-Guidelines Heart Failure A.S.I.A. Program in Taiwanese hospitals

Introduction: The American Heart Association (AHA) Get With the Guidelines – Heart Failure program has been implemented for years in the United States with extensive literature supporting its benefits. In 2022, the AHA Heart Failure Adherence to Science Implementation in Asia (HF A.S.I.A.) powered by Get With The Guidelines program was first introduced in five Asian countries. Research Question: This study aims to explore the impact of this program's implementation in Taiwanese hospitals. Methods: Data were sourced from the Taiwan Society of Cardiology-HF-Registry 2020, a prospective registry that tracks HF cases from 27 hospitals in Taiwan between 2020 and 2024. Among these, four hospitals began participating in the HF A.S.I.A. program in January 2022. This study compared patients from hospitals that participated and did not participate in the HF A.S.I.A. program. Results: A total of 1,933 HF patients with a left ventricular ejection fraction ≤ 40% were included, comprising 460 participants from the HF A.S.I.A. program and 1,473 non-participants. The HF A.S.I.A. group was younger, had significantly lower systolic blood pressure, larger left ventricular diameter, and experienced more frequent prior hospitalizations for HF. However, there were no significant differences between the two groups in terms of baseline heart rate, estimated glomerular filtration rate, blood potassium levels, and most comorbidities. During the study period, due to changes in payment policies, the use of angiotensin receptor neprilysin inhibitor (ARNI) decreased in the non-participant group, while the use of sodium glucose co-transporter 2 inhibitor (SGLT2i) increased. Conversely, the use of ARNI in the HF A.S.I.A. group continued to rise in line with guideline recommendations and the usage of SGLT2i was higher than in the non-participant group. After adjustment, one-year lost to follow-up rate was significantly lower (3.0% vs. 5.6%, p =0.032) and all-cause mortality rate trended non-significantly lower (7.6% vs. 11.4%, p =0.096) among the HF A.S.I.A. group. Conclusion: Despite enrolling sicker patients, participation in HF A.S.I.A. program was associated with higher quality of HF care.

Abstract 4133830: Uncovering the Gaps: Analyzing Prescribing Patterns of Combination Therapy with SGLT2-inhibitors and GLP-1 Receptor Agonists in Established Atherosclerotic Cardiovascular Disease (ASCVD) and Type 2 Diabetes (T2DM)

Introduction: Combination therapy with SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP1RA) reduces major cardiovascular events (MACE) and improves HbA1c, blood pressure, weight, and renal disease progression. The European Society of Cardiology recommends this therapy for ASCVD and T2DM, independent of HbA1c. This study evaluates prescribing patterns in the Internal Medicine Residency Clinics for patients with ASCVD and T2DM. Aims: To investigate demographic and social determinants of health (SDOH) influencing the prescription of combination therapy versus no therapy in an outpatient population and identify factors affecting prescribing patterns and guideline adherence. Methods: We reviewed 828 electronic records of T2DM and ASCVD patients from March 2024. Patients were grouped into combination therapy (SGLT2i and GLP1RA) and no therapy groups. Data on demographics (Table 1) and SDOH (Table 2) were analyzed. Patients on monotherapy or those who did not complete the SDOH questionnaire were excluded. Descriptive statistics were used to summarize demographics. Welch’s t-test compared continuous variables, and chi-square or Fisher’s exact tests compared categorical variables. Analyses were done with SAS 9.4 with significance at 0.05. Results: Age significantly differed between groups (t = 4.56, p < .05), with older patients less likely to receive therapy. Sex was also significant (p < .05); more females were in the no therapy group. No significant association was found between SDOH and combination therapy (p > .05). Conclusion: Over 90% of patients with T2DM and ASCVD were not on optimal medical therapy to reduce MACE, with nearly half on no medications. This highlights the need for increased awareness and targeted interventions to improve outcomes. Future research will explore insurance status and physician awareness to address prescription discrepancies. Limitations: Patients with a GFR <30 are precluded from SGLT2i usage but were not excluded from this study.

Abstract 4115947: Empagliflozin Inhibits the Mobilization of CCR2+ Monocyte-Derived Macrophages by Reducing CCL2 Expression in Fibroblasts and Slows the Progression of Heart Failure After Pressure Overload.

Background: The positive effects of sodium glucose co-transporter-2 (SGLT2) inhibitors on reducing cardiovascular mortality and hospitalizations due to heart failure have been well established. Although numerous theories propose explanations for the cardioprotective actions of SGLT2 inhibitors, these hypotheses primarily rely on initial findings and require further validation. Studies have shown that immune cells, particularly macrophages marked by C-C chemokine receptor type 2 (CCR2), contribute to the progression of heart failure by infiltrating the myocardium and inducing detrimental structural changes following myocardial infarction or pressure overload. Purpose: This study aims to investigate whether SGLT2 inhibitors can mitigate heart damage by inhibiting the migration of CCR2+ monocyte-derived macrophages. Methods: In this experiment, male B6 mice were subjected to transverse aortic constriction (TAC) to induce heart failure. Two weeks post-TAC, with heart function confirmed as equal across all groups by echocardiography, one group began receiving daily oral doses of empagliflozin, while another served as the control. At four weeks post-TAC, cardiac function was reassessed. The animals were then euthanized, and their hearts were analyzed using flow cytometry, staining, and qPCR to evaluate heart failure and the involvement of immune cells. Additionally, isolated cardiac fibroblasts were subjected to cyclic stretching to mimic post-TAC mechanical stress. Results: Treatment with empagliflozin resulted in improved cardiac function and reduced congestion in the heart and lungs, indicating alleviation of heart failure. The treatment notably decreased myocardial fibrosis, evident from Picrosirius-red staining and reduced expression of fibrosis-related mRNA. Importantly, empagliflozin specifically reduced the number of CCR2-positive macrophages in the heart, without affecting other types of immune cells. In cardiac fibroblasts that underwent cyclic stretching, empagliflozin pre-treatment diminished the expression of C-C motif chemokine ligand 2 (CCL2), the ligand for CCR2. Conclusion: Empagliflozin’s ability to suppress CCL2 expression in fibroblasts and curtail the recruitment of CCR2+ macrophages may represent a potential strategy to decelerate heart failure progression. These findings advance our understanding of the cardioprotective mechanisms of SGLT2 inhibitors and propose novel therapeutic avenues for heart failure management.

Abstract 4140181: Mechanisms of SGLT-2 Inhibitor Empagliflozin in Attenuating Intramitochondrial Stress and Restoring Mitochondrial Function in Hyperglycemic Cardiomyocyte

Systemic hyperglycemia causes tissue damage and triggers cardiovascular disease (CVD). Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) are a novel class of glucose-lowering agents that have shown unexpected benefits in clinical trials for the treatment of CVDs. We aim to investigate the underlying mechanisms of how SGLT-2 inhibitors alleviate CVDs associated with elevated glucose stress. iPSC-derived cardiomyocytes (iPSC-CM) were incubated with high glucose concentrations for 72 hours. Mitochondrial function in these cardiomyocytes was assessed by flow cytometry with JC-1 staining and ATP luminescence assay. Intracellular reactive oxygen species (ROS) and intramitochondrial calcium stress were measured using CellROX, MitoSOX, and Rhod-2 AM staining. Patch clamp was employed to determine ion current changes in the cardiomyocytes. Mitochondrial oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were determined using the Seahorse XFe96 analyzer. In addition, qPCR, Western blot, and DM mouse heart histological analysis were performed to assess the regulation of associated molecules. The results indicated that exposure to a high glucose environment caused cardiomyocyte injury and impaired mitochondrial biosynthesis. Empagliflozin exhibited a beneficial effect on mitochondrial function by reducing ROS production and calcium deposition. It also mitigated the reduction in respiratory OCR of cardiomyocytes induced by high glucose incubation. Furthermore, molecular analysis revealed that Empagliflozin attenuated the dysregulation of mitochondrial calcium channels and biosynthesis by reducing associated gene expression, including Bcl2 , Mfn1 , Mx2 , Oas1 , Ant3 , Mcu , Micu1 , Vdac1 , Ryr2 , and Cypd-ppid . Histological analysis of DM mouse hearts demonstrated that reduced MFN2 and ZBP1 were target molecules for hyperglycemia-induced reduction of calcium channel currents in cardiomyocytes and could be restored by Empagliflozin treatment. This study concludes that high glucose stress diminishes mitochondrial calcium channel regulators MFN2 and ZBP1 in cardiomyocyte, which reduces calcium channel currents and leads to sensitization of cardiomyocyte to arrhythmogenesis, resulting in VT/VF. It provides experimental evidence for the clinical efficacy of Empagliflozin in ameliorating CVDs and managing diabetes-related CVDs.

Abstract 4135480: Effect of Time Since Heart Failure Diagnosis or Hospitalization on the Cost-effectiveness of Dapagliflozin in Patients with Heart Failure with Mildly Reduced or Preserved Ejection Fraction

Background: Previous studies have shown dapagliflozin, a sodium-glucose co-transporter-2 inhibitor (SGLT2i), to be a cost-effective treatment option for patients with heart failure (HF) with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF) in multiple European settings. Research question: Is the cost-effectiveness of dapagliflozin treatment in HFpEF/HFmrEF modified by either the time since HFpEF/HFmrEF diagnosis or the time since the last hospitalization for heart failure (HHF) event? Methods: A Markov cohort transition model was built for the UK setting, informed by patient-level data from the randomized, placebo-controlled DELIVER trial. The patient population was subset according to categories of time since last HHF event (including no prior HHF) and time since HF diagnosis (further subset to those with no prior HHF). For each subgroup, disease evolution was characterized by transitions among health states defined by quartiles of the Kansas City Cardiomyopathy Questionnaire Total Symptom Scale. The risk of fatal (cardiovascular and non-cardiovascular) and non-fatal events of worsening HF were modelled, adjusting for baseline characteristics and time-updating health state. Incremental costs and quality-adjusted life-years (QALYs) were calculated for each subgroup to yield incremental cost-effectiveness ratios (ICERs). Results: The lowest ICERs were observed for subgroups with the shortest time from HF diagnosis (with and without prior HHF) or last HHF event (Figure 1). Across all subgroups, the calculated ICERs were below the UK willingness-to-pay (WTP) threshold of £20,000/QALY gained. Conclusions: In patients with HFpEF/HFmrEF, the cost-effectiveness of dapagliflozin improved (via lower ICERs) in the subgroups corresponding to earliest disease (least time since an HHF event or HF diagnosis) compared with groups of later disease and potentially delayed treatment initiation. These findings suggest early optimization of HF therapy with implementation of guideline-directed medical therapy, including SGLT2is, may improve economic value.

Abstract 4137996: Effects of Empagliflozin on diuresis in heart failure: Results from the CINNAMON-study and in-vivo experiments

Background and Purpose: Heart failure is associated with renal dysfunction suggesting a pathophysiological link between heart and kidney. Empagliflozin, a SGLT2 inhibitor, showed beneficial effects on both cardiovascular and renal endpoints. However, mechanistically, it is unclear if empagliflozin-dependent kidney protection is mediated via inhibition of tubular SGLT2 or more indirectly via improved cardiac function. We hypothesized that Empagliflozin treatment improves left ventricular ejection fraction (LVEF) independent of diuretic effect of renal SGLT2 inhibition. Methods: We evaluated NTproBNP, hematocrit, hemoglobin and bodyweight in patients with HF with reduced (n=32) and preserved ejection fraction (n=59) after 30 and 180 days (prospective, single-arm CINNAMON-study, DRKS00031101). Furthermore, we conducted transverse aortic constriction (TAC) or sham surgery in C57BL/6J (wildtype, WT) and SGLT2 deficient mice (SGLT2 -/- ). Animals received either Empagliflozin (10 mg/kg bodyweight) or vehicle by daily oral gavage. Water intake and output was evaluated by metabolic cages at 10 weeks and cardiac function by echocardiography. Results: Empagliflozin treatment reduced NT-proBNP levels and increased hematocrit and hemoglobin levels especially in patients with reduced ejection fraction (Fig. A-C). Surprisingly, there was no change in body weight (Fig. D), which would be expected if the diuretic effects were dominant. In mice after 10 weeks, echocardiography confirmed TAC induced pressure-overload, leading to reduced LVEF. Empagliflozin attenuated changes in LVEF (Fig. G) and improved diastolic dysfunction (isovolumetric relaxation time, data not shown). To test if direct inhibition of SGLT2 in the heart and kidney is mechanistically involved, TAC surgery was repeated in SGLT2-deficient mice (SGLT2-KO). In fact, exposure to TAC resulted in comparable reduction of LVEF in SGLT2-KO and Empagliflozin prevented this deterioration similar to WT mice (Fig. G vs. I). Surprisingly, Empagliflozin did not increase drinking and urine volume neither in wildtype nor in SGLT2 deficient mice, suggesting a mechanism of cardioprotection independent of diuretic effects. Conclusion and Outlook: This is the first study investigating the role of SGLT2 in Empagliflozin treated patients and mice with heart failure. Importantly, empagliflozin treatment prevented deterioration of LVEF independent of the presence of SGLT2 and diuresis.

SGLT2 inhibitors and diabetic retinopathy: Insights from the management of nephropathy

SGLT2 inhibitors and diabetic retinopathy: Insights from the management of nephropathy

Abstract 4126262: The impact of angiotensin receptor neprilysin inhibitors on the elderly population with heart failure and reduced ejection fraction: data from the real world

Heart failure (HF) remains a disease of increasing prevalence and morbidity. Validation of new lines of therapy in the elderly are required due to the progressive ageing of the world's population and scarce evidence in elderly patients with HF with reduced ejection fraction (HFrEF). The purpose of our study is to analyse the effect of Angiotensin Receptor–Neprilysin Inhibitors (ARNI) in this subgroup of patients. We conducted a single-centre, real-world observational study. We consecutively enrolled all patients aged ≥75 years diagnosed with HFrEF (defined as an ejection fraction <40%) and theorical indication for treatment with ARNI from November 2019 to January 2021. The main outcomes analysed were all cause mortality and admission due to HF. In order to avoid potential confounding factors, we performed a propensity-score (PS) matched analysis. Patients matching was performed in a 1:1 ratio with the nearest neighbour method. A total of 364 patients were recruited (total population). The mean age was 84.1 years of which 67% were male. 81% were hypertensive and 33.5% diabetic. The main cause of ventricular dysfunction was ischemic with 50.2%. At inclusion 55.8% were in NYHA functional class II and the mean LVEF was 29.8%. After PS matching, we selected 184 patients (study population), 92 with ARNI. As compared with non ARNI group, the ARNI patients showed higher use of mineralocorticoid receptor antagonists (MRA) (59.8% vs 43.5%, p< 0.05) and SGLT2 inhibitors (40.2% vs 6%, p<0.05). Other treatments were otherwise similar in both groups. There were not significant differences in relation with age, etiology or comorbidities between ARNI group and non-ARNI group. During a median follow-up of 39 months, total mortality was 31.5% (58 patients). After a Cox logistic regression analysis, ARNI therapy was shown to be an independent protective variable with respect to total mortality [HR 0.6 (0.4-1), p 0.05]. The figure shows the Kaplan-Meier survival curves for total mortality in patients with and without ARNI treatment. In summary, treatment of HFrEF remains a significant challenge in managing HF patients, especially in the elderly. According to our data, treatment with ARNI in elderly patients with HFrEF was associated with a lower rate of all-cause mortality. Our data show us that ARNI therapy could improve prognosis in the elderly with HFrEF in a real-world study.

Abstract 4116975: Safety signals with SGLT2 inhibitor use in diabetic males with erythrocytosis, but not in females: Findings from the CANVAS Program and CREDENCE trial

Backgrounds: Mediation analyses have shown that an increase in hematocrit (Hct) levels significantly contributes to the cardiorenal benefits of SGLT2 inhibitors (SGLT2i). However, given the link between erythrocytosis and poor prognosis, concerns remain about whether SGLT2i-induced erythropoiesis in patients with erythrocytosis may increase thromboembolic events (TE) including myocardial infarction (MI). Methods: We conducted a pooled analysis utilizing individual participant data from the CANVAS Program and the CREDENCE trial, both aimed to evaluate the efficacy and safety of canagliflozin versus placebo in diabetic patients. The primary outcome was a composite of MI, stroke, or any other TE. Sex-specific Cox analyses were performed to assess effect modifications by baseline Hct levels, treated as categorical (anemia, normal, and erythrocytosis) or continuous variable. Results: Of the participants for whom baseline Hct values were available (98.5% [14,321/14,543]), 35% were female. Canagliflozin significantly increased the percentage of erythrocytosis from baseline to 1 year in males (5.6% to 16.9%) and females (1.9% to 5.2%), unlike placebo. Overall, canagliflozin did not alter the risk of the primary outcome for either male (HR 0.97; 95% CI, 0.86–1.10) or female (HR 0.95; 95% CI, 0.78–1.15). In males, baseline Hct levels modified treatment effect on the primary outcome, whether treated as categorical or continuous variables (Pinteraction <0.05), with benefits in anemic patients and harm in those with erythrocytosis (Figure). Meanwhile, no effect modifications were noted in females. In analyses for each component of the primary outcome, canagliflozin consistently reduced the risk of MI, stroke, and any TE in anemic male patients (HR 0.53, 0.49, and 0.71, respectively). However, mixed results were observed in those with erythrocytosis (HR 1.77, 0.62, and 1.11, respectively), suggesting detrimental effects on the primary outcome in these patients were primarily driven by MI. No heterogeneity by Hct was found for heart failure hospitalization or kidney outcome in both sexes. Conclusion: Canagliflozin may pose a safety concern regarding the risk of TE in diabetic male patients with erythrocytosis.

Abstract 4134483: How succesfully can we presribe the 'four pillars' of medications for patients with heart failure with reduced LV systolic function?

Introduction: European, American and UK guidelines all endorse the prescription of the 'four pillars' of treatment (ACE/ARBs, b-blockers, MRAs and SGLT2 inhibitors) for heart failure with reduced LV systolic function (HFrEF). Many doctors believe that it is difficult to initiate and maintain patients on all these medications. We have studied 162 consecutive patients referred to our service as outpatients from primary care, subsequently diagnosed as having HFrEF, and our ability to establish them on these medications. Methods: Patients referred with potential heart failure (signs, symptoms and raised BNP) were identified as having HFrEF by echocardiography using British Society of Echocardiography (BSE) criteria. Patients attended regular outpatient appointments with a consultant cardiologist and specialist heart failure nurse and were prescribed and uptitrated all appropriate medications with any contraindications and intolerances noted. Results: Table 1 shows the number of patients sucessfully established on maximally tolerated doses of each class of medication. Reasons for not prescibing or discontinuing were: CKD 6, severe aortic stenosis 5, asthma 3, symptomatic bradycardia 5, hypotension 3, type1 diabetes 2, syncope 1, Raynauds 1, patient choice 8 and 6 patients died before all appropriate medications could be initiated. In 10 cases no clinical reason could be identified. It can be seen that a high proportion of patients were successfully established on each individual class of medication and more than two thirds of patients were able to be maintained on all four classes of therapy. Table 2 shows the breakdown of prescribing success according to the severity of LV dysfunction. It can be seen that prescribing success appears to be higher in those with the more severe LV dysfunction. Conclusions: 1. The majority of patients can be established and maintained on appropriate polypharmacy for the treatment of LV systolic dysfunction. 2. The severity of LV systolic dysfunction is not a negative predictor of success in prescribing.

Abstract 4113486: Cardiovascular Benefits of Sotagliflozin in Diabetic Populations: A Meta-Analysis

Background: Sotagliflozin, an inhibitor of both SGLT1 and SGLT2, is under investigation for potential cardioprotective effects in diabetic patients. Aims: This study assesses the efficacy and cardiovascular benefits of sotagliflozin in patients with type 1 or type 2 diabetes at high cardiovascular risk or with diagnosed heart failure. Methods: We systematically searched digital databases including ClinicalTrials.gov, PubMed, Google Scholar, Cochrane, Medline, and Embase, using a PICOS-based strategy and the PRISMA framework for data reporting. Randomized controlled trials comparing sotagliflozin against placebo over a minimum duration of eight weeks were analyzed using Review Manager (RevMan) 5.4.1. Results: Our meta-analysis included 7 studies with 16,315 participants with all studies comparing either 200 or 400 mg sotagliflozin to placebo. The meta analaysis revealed significant improvements in reduction the total number of cardiovascular deaths [OR= 0.70 (95% CI (0.51- 0.95)), p = 0.02]; reduction in Non-fatal MI [OR=0.76 (95% CI (0.70- 0.84)), p < 0.00001]; reduction in the incidence of hospitalizations due to HF [OR=0.54 (95% CI (0.44, 0.66)), p < 0.00001]; reduction In urgent hospitalizations [OR=0.66 (95% CI (0.53, 0.83)), p=0.0004]; improvement in LVEF>50% [ OR= 0.41 (95%CI (0.34, 0.51)), p<0.0001] and reduction in systolic blood pressure mean reduction of -0.81 (95% CI (1.36, -0.25)), p=0.005]. However there was no statistically significant reduction in all cause mortality [0.73 (95% CI (0.42, 1.26)), p=0.26] . Conclusion: Sotagliflozin significantly reduces the incidence of cardiovascular deaths, adverse events, and hospitalizations in diabetic patients at high risk of cardiovascular complications.

Abstract 4134384: Sotagliflozin, a Dual Inhibitor of Sodium-Glucose Transporters 1 and 2, Elicits Cardioprotective Effects Through Attenuation of Platelet Activation and Thrombosis

Sodium-glucose cotransporter (SGLT) inhibitors are used in the treatment of type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). In the SCORED trial, sotagliflozin (SOTA), a dual SGLT1/2 inhibitor, demonstrated significant reductions in both myocardial infarction (MI) and stroke in patients with T2DM and CKD. These results suggest a cardiovascular (CV) benefit of SOTA in patients with T2DM and CKD who are at increased risk of thromboembolic disease. To investigate the underlying mechanism of CV protection, we evaluated the effects of SOTA on platelet activation and thrombus formation, in both in vivo and ex vivo models, to understand its effects on MI and stroke. Washed human platelets treated with SOTA were stimulated with various agonists and platelet activation was assessed via lumi-aggregometry and flow cytometry. In whole blood, SOTA was evaluated for its potential to reduce platelet adhesion and thrombus formation in the perfusion flow chamber and Total Thrombus formation Analysis System (TTAS) assays. In vivo , mice dosed with SOTA were assessed for thrombus formation at the site of injury in real-time in the cremaster arteriole injury model. To determine the effect of SOTA on hemostasis, we assessed coagulation parameters ex vivo in human whole blood using thromboelastography. Finally, bleeding time was measured in vivo in mice dosed with SOTA using the tail bleeding assay. In washed platelets, SOTA inhibits platelet activation and aggregation in a dose-dependent manner. Similarly, a dose-dependent decrease in platelet adhesion and thrombus formation was observed in whole blood assays. In vivo , platelet accumulation and fibrin formation were decreased in mice dosed with SOTA, however no effect is observed in coagulation parameters or bleeding time. SOTA inhibits platelet activation and thrombus formation with no impact on coagulation parameters or bleeding potential. These findings highlight a potential mechanism through which SOTA reduces the risk of stroke and MI in patients with T2DM and CKD, underscoring the importance of further investigation into the role of SOTA in CV protection, particularly in patients suffering from both T2DM and CKD at high risk of thromboembolic events.

DIABETES MELLITUS E SUAS IMPLICAÇÕES RENAIS: UMA REVISÃO BIBLIOGRÁFICA FOCADA NA NEFROPATIA DIABÉTICA E INSUFICIÊNCIA RENAL CRÔNICA

The article explores the renal complications of diabetes mellitus (DM), focusing on diabetic nephropathy (DN) and chronic renal failure (CRF). DN, considered one of the main causes of CRF in the world, results in high rates of morbidity and mortality in diabetic patients. The article addresses the pathophysiology of these diseases, highlighting how chronic hyperglycemia in DM leads to a series of structural and functional changes in the kidneys. Mechanisms such as advanced protein glycation, oxidative stress, activation of inflammatory cytokines, and endothelial dysfunction are central to the progression of DN. In addition to pathophysiology, the article extensively discusses treatments available to slow the progression of DN and prevent CKD. Strict control of glycemic levels, through medication and lifestyle changes, is essential. Furthermore, the use of drugs such as ACE inhibitors and angiotensin II receptor blockers has shown beneficial effects on renal protection. Other emerging treatments include SGLT2 and GLP-1 inhibitors, which demonstrate efficacy in both glycemic control and preservation of renal function. The article concludes that prevention and adequate management of these complications are fundamental to improving patients' quality of life and reducing rates of progression to CKD.

Effects of sodium-glucose cotransporter-2 inhibitor on atrial high-rate episodes in patients with cardiovascular implantable electronic device: a randomized controlled trial

Effects of sodium-glucose cotransporter-2 inhibitor on atrial high-rate episodes in patients with cardiovascular implantable electronic device: a randomized controlled trial

Abstract 4134947: Explainable Machine Learning to Predict Heart Failure Outcomes Using Exercise and Clinical Data

Background: Heart failure (HF) hospitalizations are associated with disease burden and cardiovascular mortality. International guidelines highlight cardiopulmonary testing (CPET) for risk stratification and prognosis in HF. Identifying individuals at risk could direct interventions to prevent admissions. This study uses explainable machine learning (XML) tools to identify CPET and clinical variables predictive of HF hospitalizations. Hypothesis: XML analysis of CPET parameters and clinical factors can yield accurate, patient-specific prediction of HF admission within one year. Methods: A retrospective single center review of 178 CPETs in patients referred for HF was completed. Clinical data within one year of CPET trained a boosted machine learning model (XGBoost). SHAP (Shapley Additive Explanations) explainability analysis emphasized key features for model predictions. Results: 44 (24.7%) patients with CPET were admitted for HF within one year. The model predicted this outcome with an area under the receiver operating characteristic curve (AUC) of 0.772. SHAP analysis (Figure 1) selected factors for decision making: pulmonary artery systolic pressure (PASP) via cardiac catheterization or echocardiogram; oxygen consumption at the ventilatory threshold (VO 2 at VT); O 2 pulse at rest; ventilatory efficiency (VE/VCO 2 slope); minute ventilation per oxygen consumption at maximal exercise (VE/VO 2 max) during CPET; left ventricle end diastolic volume by echocardiogram; and sodium-glucose cotransporter-2 inhibitor usage. Peak VO2, predicted VO2, predicted O2 pulse, and VE/VCO2 slope were significant, consistent with past studies (Table 1). Conclusion: Our XML analysis emphasizes PASP (partially related to high left ventricular filling pressures) and VO 2 (at ventilatory threshold) as predictive for HF hospitalization within one year of CPET testing. Studies to prospectively evaluate these highlighted factors are needed to continue exploring predictive capabilities to tailor interventions.

Abstract 4116177: Metabolic and Pharmacokinetic Profiling of Ketone Ester by Background SGLT2 Inhibitor Therapy in Heart Failure with Reduced Ejection: A Phase I Clinical Trial

Background: Growing evidence supports a therapeutic role for ketones in HFrEF. However, no pharmacokinetic (PK) studies are available to guide further investigation, and uncertainty exists regarding use with the ketogenic SGLT2i and dose-dependent effects. Methods: We conducted a phase I trial of two doses of ketone ester (KE, 250 mg/kg and 500 mg/kg) in 20 HFrEF participants, stratified by SGLT2i use. Non-compartmental analysis assessed PK parameters of ketones. Paired t-tests and generalized linear mixed models assessed changes in mass-spectrometry based targeted metabolites, blood gas, and vital sign assessments up to 4 hours after dosing. Results: The mean age was 66.0±14.8 years, 45% were women, 30% were non-White, and average EF was 33±13%. The median (25 th –75 th percentile) T max , C max , and T 1/2 for total ketones with 250 and 500 mg/kg doses were 1.01 (0.64-1.24) and 1.58 (1.06-1.99) hours, 2317 (2165-2491) and 3354 (3291-3538) µM, and 0.85 (0.66-1.24) and 2.04 (1.36-3.47) hours, respectively ( Figure 1A ). One hour after KE consumption, insulin levels robustly increased, while non-esterified fatty acids, branched-chain amino acids, and acylcarnitines decreased except for C2/C4-OH acylcarnitines, which increased (FDR-adjusted p-value<0.05). Increases in ketones and C2/C4-OH acylcarnitines were dose-dependent, while background SGLT2i was associated with blunting of the decrease across acylcarnitines. One hour post KE, heart rate initially rose by 4 (95%CI 2-6) beats/min, while systolic blood pressure (-7, 95%CI -12, -2 mmHg), pH (-0.07, 95%CI -0.08, 0.05), and bicarbonate (-3, 95%CI -4, -2 mEq/L) decreased, with dose-dependent acid-based effects ( Figures 1B-C ). These values returned close to baseline by 4 hours. Adverse events were infrequent and mild. Conclusions: Acute KE ingestion is associated with rapid changes in several key metabolic pathways, with differential effects imparted by background SGLT2i (fatty acid metabolism) and dose (ketone metabolism). Hemodynamic effects were transient and irrespective of dose/SGLT2i, while acidotic effects were heightened with increasing dose. These data support the safety of combined KE and SGLT2i in HFrEF and provide grounding data for further trials.

Abstract 4138716: A novel Urocortin-2 analog COR-1167 corrects cardiac and renal dysfunction on top of Empagliflozin in a rat model of acute decompensated heart failure

Introduction: Urocortin-2 (UCN-2) is a peptide belonging to the corticotropin-releasing factor family that has cardiovascular, renal, metabolic and anti-inflammatory actions and improves cardiac function in human heart failure (HF) and cardiorenal dysfunction in chronic HF models. However, UCN-2 has a short half-life and intravenous delivery limits its therapeutic use. COR-1167 was discovered as a stable UCN-2 analog with qd pharmacological effects when injected subcutaneously. Hypothesis: Whether COR-1167 exerts chronic cardiorenal protection in Acute Decompensated HF (ADHF) is unknown, and in particular on background of SGLT2 inhibition, therefore both treatments were tested in a rat model of ADHF. Methods: Rats had coronary artery ligation to induce MI and a reduced ejection fraction phenotype. Three months later, rats were treated with vehicle or Empagliflozin (Empa) at 10 mg/kg/day PO. One month after starting Empa, two acute decompensation events were induced by administrating NaCl solution (1.8 g/kg, PO) on Day 0 and Day 14. Empa treated ADHF rats received vehicle or COR-1167 (3 µg/kg/day) by SC injections starting at 12 hours after the first decompensation and all treatments continued for 14 days. The groups were ADHF, ADHF + Empa and ADHF + Empa + COR-1167 (n=7-10/group). Left ventricular (LV) hemodynamics (cardiac catheters), cardiac output (echocardiography) and LV tissue perfusion (magnetic resonance imaging), cardiac mitochondrial coupling and ATP production (Seahorse) were measured 1 day after the second decompensation, while urine volume (uVol) and urine Na + excretion (uNa + ) collected from metabolic cages were analyzed 7 days after the first decompensation. Results: Compared to ADHF control rats, Empa treatment had no effect on systolic blood pressure (SBP), cardiac output (CO), LV end systolic pressure volume relationship (LVESPVR), LV end diastolic pressure volume relationship (LVEDPR), mitochondrial coupling and ATP production, but it increased myocardial perfusion, uVol and uNa + excretion. Compared to ADHF + Empa rats, COR-1167 treatment increased SBP, CO, LVESPVR, myocardial perfusion, mitochondrial coupling and ATP production, uVol, uNa + , while decreasing LVEDPVR. Conclusion: In the setting of ADHF, significant cardiorenal benefits and decongestion occurred when COR-1167 was administered on top of an SGLT2 inhibitor.

Social Determinants of Health and Disparities in Guideline-Directed Medical Therapy Optimization for Heart Failure

BACKGROUND: Fewer than 20% of eligible patients with heart failure with reduced ejection fraction receive all 4 pillars of guideline-directed medical therapy. Understanding disparities by race, ethnicity, sex, and adverse social determinants of health is necessary to equitably optimize quadruple therapy. METHODS: Utilizing the American Heart Association’s Get With The Guidelines-Heart Failure registry, we examined associations between race and ethnicity, sex, and adverse social determinants of health (insurance type and documented social need [any barrier to accessing health care]) with quadruple therapy optimization (QTO) in patients with heart failure with reduced ejection fraction hospitalized between July 1, 2021, and September 30, 2023, with complete medication data at discharge. We calculated adjusted mean differences (AMDs) in the discharge QTO score (range, 0%–100%) reflecting the proportion of eligible use of renin-angiotensin system inhibitors, β-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter-2 inhibitors and compared across demographic and adverse social determinants of health groups. RESULTS: Among 82 637 patients (median age, 66 years; 32.5% female; 57.0% non-Hispanic White; 76.4% prior heart failure with reduced ejection fraction), the overall mean QTO score was 56.2% (SD, 25.5). After adjustment, compared with non-Hispanic White individuals, Black (AMD, 2.56 percentage points [95% CI, 2.16–2.96]) and Hispanic individuals (AMD, 0.71 percentage points [95% CI, 0.11–1.31]) had higher QTO scores. Females had higher QTO scores than males (AMD, 1.94 percentage points [95% CI, 1.58–2.31]). Patients with no insurance (AMD, −4.90 percentage points [−5.62 to −4.17]), Medicaid (AMD, −0.45 percentage points [−0.89 to −0.01]), and Medicare (AMD, −1.64 percentage points [−2.10 to −1.18]) had lower QTO scores versus private insurance. Those with an identified social need (n=24 651) had lower QTO scores than those without (AMD, −3.40 percentage points [95% CI, −4.10 to −2.71]). CONCLUSIONS: Disparities in QTO were most evident for patients with no insurance, Medicaid, Medicare, or potentially an identified social need. Future efforts should focus on reducing gaps to improve equitable guideline-directed medical therapy use.

Dumping syndrome: Update on pathophysiology, diagnosis, and management

AbstractBackgroundDumping syndrome is a complex of gastrointestinal symptoms originally studied in peptic ulcer surgery patients. At present, it is most prevalent in patients who underwent bariatric, upper gastrointestinal cancer or anti‐reflux surgery. The symptom pattern comprises early and late dumping symptoms. Several management options have been reported including nutritional, pharmacological and surgical approaches.Aims and MethodsIn this study, we aimed to review the current evidence on dumping syndrome definition, diagnosis and treatment, including preliminary data from newer pharmacological studies.ResultsCurrent pathophysiological concepts and analyses of provocative tests has led to a clear definition of dumping syndrome, including both early and late dumping symptoms. The term postbariatric hypoglycemia represents a limited focus on late dumping only. The diagnosis relies on recognition of symptoms and signs in a patient with appropriate surgical history; and can be confirmed by provocative testing or registration of spontaneous hypoglycemia. The initial treatment focuses on dietary intervention, to which meal viscosity enhancers and/or the glycosidase inhibitor acarbose can be added. The most effective therapy is the use of short‐ or long‐acting somatostatin analogues, which is however expensive and entails side effect issues. In case of refractory hypoglycemia, diazoxide or SGLT2 inhibitors can be considered, based on limited evidence. In refractory patients, continuous enteral feeding or (rarely) surgical reinterventions have been advocated, although not supported by solid evidence. Therapies under current evaluation include the broad‐spectrum somatostatin analogue pasireotide, GLP‐1 receptor antagonists, GLP‐1 receptor agonists and administration of stable forms of glucagon are currently under study.ConclusionsDumping syndrome is a well‐defined but probably under‐diagnosed complication of upper gastrointestinal, especially bariatric, and surgeries. Diagnosis is confirmed by a provocative test and incremental therapies starting with diet, adding meal viscosity enhancers or glycosidase inhibitors and adding somatostatin analogues in refractory cases. A number of emerging therapies targeting intestinal propulsion, peptide hormone effects and hypoglycemic events are under evaluation.

Sodium-Glucose Cotransporter 2 Inhibitors Improve Body Composition by Increasing the Skeletal Muscle Mass/Fat Mass Ratio in Patients with Type 2 Diabetes: A 52-Week Prospective Real-Life Study

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2is) induce body weight loss, but their effect on skeletal muscle mass (SMM) and strength needs to be better elucidated. Objectives: This study aimed to evaluate the effects of SGLT2i on SMM in a real-life population setting of patients with type 2 diabetes (T2D). Secondary outcomes included changes in liver steatosis and in anthropometric and glucometabolic parameters. Methods: Seventy-one patients were treated with SGLT2is as an add-on to metformin for 52 consecutive weeks. Visits were scheduled at baseline (T0) and after 6 (T6) and 12 months of therapy (T12) and included the checking of laboratory tests, measurement of anthropometric parameters, bioimpedance analysis of body composition, and abdominal ultrasound (US). Results: Fat mass (FM) and visceral adipose tissue (VAT) progressively decreased compared to the baseline (FM: −2.9 ± 0.6 kg at T6; −2.8 ± 0.6 kg at T12; VAT: −0.3 ± 0.1 L at T6; −0.4 ± 0.1 L at T12; all p < 0.01). Changes in SMM were less pronounced (−0.4 ± 0.3 kg at T6, ns; −0.7 ± 0.4 kg at T12, p < 0.05), yielding a beneficial increase in the SMM/FM ratio (+0.3 ± 0.05 at T6 and +0.2 ± 0.05 at T12, all p < 0.01). No significant changes in sarcopenia, sarcopenic obesity, fat-free mass, muscle strength, and water compartments were observed at the end of the follow-up period. Anthropometric and glucometabolic parameters, insulin resistance, liver enzymes, and biometric indices and US grading of hepatic steatosis improved throughout this study. Conclusions: In a real-life setting, SGLT2i therapy is associated with weight loss attributable to FM rather than SMM loss without any relevant deterioration in muscle strength. In addition, SGLT2is proved to have beneficial effects on steatotic liver disease.