SGLT2 Inhibitors Research Articles

Abstract 4134974: SGLT2 Inhibitors Following Acute Myocardial Infarction: A Systematic Review and Meta-Analysis

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have demonstrated cardiovascular benefits in various settings. However, their impact after myocardial infarction (MI) in patients without prior heart failure remains unclear. Therefore, we conducted a meta-analysis comparing SGLT2i to placebo in post-MI patients. Methods: We systematically searched Pubmed, Embase, and Cochrane Central for randomized controlled trials (RCTs) comparing SGLT2i to placebo in post-MI patients. We calculated the Risk Ratio (RR) for binary outcomes and 95% confidence intervals (CI). Statistical analysis was performed using Review Manager 5.4. A random-effects model was used for all outcomes. Heterogeneity was examined with I2 statistics. Results: We included 3 RCTs comprising 11,065 patients in this meta-analysis, where 79.5% were male with a mean age of 61.9 years old. Two studies evaluated Empaglifozin and one Dapagliflozin. There was no statistically significant difference between groups in all-cause mortality (RR 1.05; 95% CI 0.78-1.41; p= 0.76; Figure 1A) and cardiovascular mortality (RR 1.04; 95% CI 0.84-1.29; p= 0.73; Figure 1B). There was a statistically significant reduction in the incidence of heart failure hospitalization in the SGLT2i group (RR 0.73; 95% CI 0.61-0.88; p< 0.01; Figure 1C). Conclusion: Our systematic review and meta-analysis found that SGLT2i significantly reduced the incidence of heart failure hospitalization in patients following MI, without significantly affecting all-cause or cardiovascular mortality.

Sodium-glucose cotransporter 2 inhibition in patients with liver cirrhosis and diabetes: a possible role in ascites control?

The aim of this brief report is to evaluate sodium-glucose cotransporter 2 inhibitors (SGLT2-I) effects on patients with both refractory ascites and type 2 diabetes mellitus (T2D). We consecutively recruited all the diabetic patients with refractory ascites due to decompensated liver cirrhosis admitted between February and May 2023 at the Internal Medicine Unit of the University Hospital of Palermo. Clinical and laboratory data were collected after starting SGLT2-I therapy. SGLT2-I use was associated with a reduction/resolution of ascites and with an improvement in serum albumin and sodium levels and estimated glomerular filtration rate. SGLT2-I might represent a valid therapeutic option in the treatment of patients with refractory ascites and T2D, as already hypothesized by other research groups.

Abstract 4136724: Early Adoption of Sodium-Glucose Cotransporter-2 Inhibitor Among Patients Hospitalized with Heart Failure and Preserved Ejection Fraction in the United States

Introduction: In August 2021, the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) found that empagliflozin reduced rates of cardiovascular death and hospitalization by 21% in patients with heart failure with mildly reduced ejection fraction of 41-49% (HFmrEF) and with preserved ejection fraction of > 50% (HFpEF). National trends in Sodium-Glucose Cotransporter-2 Inhibitors ( SGLT2i) use among patients with HFmrEF and HFpEF following this trial are unknown. Methods: We identified patients hospitalized for HFmrEF and HFpEF in the AHA Get With The Guidelines-Heart Failure registry between July 2021 and September 2023. We examined temporal trends in SGLT2i prescriptions at discharge after the publication of the EMPEROR-Preserved trial using the Cochran-Armitage trend test. Results: Among 158,849 hospitalizations with an EF > 40% across 557 hospitals, 27,712 (17.4%) had HFmrEF, and 131,137 (82.6%) had HFpEF. Overall, 22,126 (13.9%) patients were discharged with a prescription for SGLT2i, with higher rates among those with HFmrEF (18.5% vs. 13.0% in those with HFpEF). Patients prescribed SGLT2i were more likely to be younger, male, of Black race, have type II diabetes, have Medicaid insurance, and be discharged from large hospitals. After publication of the EMPEROR-Preserved trial during Q3 2021, rates of SGLT2i prescription at hospital discharge increased from 4.2% in Q3 2021 to 23.5% in Q3 2023, with a 29% relative increase in the rate of SGLT2i prescription for each quarter (adjusted OR, 1.29 [95% CI: 1.28, 1.29]; P<.001). Prescription rates increased from 6.1% in Q3 2021 to 31.6% in Q3 2023 among patients with HFmrEF and from 3.8% to 21.9% for patients with HFpEF (Figure). Conclusion: In the U.S., the use of SGLT2i at discharge has increased for patients hospitalized with HFmrEF and HFpEF following the publication of the EMPEROR-Preserved trial. However, the majority of eligible patients hospitalized for decompensated HF remain untreated with SGLT2i, indicating the need for further efforts to apply the scientific findings into clinical practice.

Abstract 4141446: Sodium Glucose Co-transporter 2 (SGLT2) Inhibitors Promote Resiliency to High Pressure Stress in the Human Microvasculature

Emerging evidence suggests that vascular stress from cardiovascular-related co-morbidities promotes microvascular dysfunction, a key component in the development of heart failure with preserved ejection fraction. The sodium glucose co-transporter 2 (SGLT2) inhibitor empagliflozin has been shown to reduce both morbidity and mortality associated with heart failure with preserved ejection fraction, however the full scope of influence of this therapy on human microvascular function remains unknown. We hypothesized that pre-treatment of isolated human microvessels with empagliflozin will prevent stress-induced endothelial dysfunction as evidenced by preserving both the magnitude of flow-induced dilation (FID) as well as the ability to dilate to nitric oxide. Human resistance arterioles (80-250µm) from healthy adults (defined as patients with ≤1 risk factor for cardiovascular disease) were dissected from discarded surgical adipose tissue and treated with empagliflozin (1µM), or vehicle control (ethanol) for 16-20 hours prior to the flow experiment. Vessels were cannulated for videomicroscopy and subjected to high intraluminal pressure (150mmHg, 30 min), an acute stress known to induce endothelial dysfunction. Vessels were pre-constricted with endothelin-1 prior to initiation of flow. A nonlinear logistic regression was used to determine differences between curves. Compared to vehicle control, vessels pre-treated with empagliflozin (1µM ) exhibited nitric oxide-dependent FID as dilation was impaired in the presence of the nitric oxide synthase inhibitor L-NAME (EC50 Control: 10.7 vs L-NAME 83.45, p=0.0107). This data suggests that empagliflozin, an SGLT2 inhibitor, promotes microvascular resilience to stress via preservation of nitric oxide-mediated FID. The ability to elicit stress resilience may explain in part some of the cardiovascular benefits associated with SGLT2 inhibitors and may offer unique opportunities for early intervention or prevention of microvascular dysfunction associated with comorbidities that contribute to heart failure with preserved ejection fraction.

Abstract 4135113: Referral to a Heart Failure Clinic Substantially Increases the Use of Angiotensin Receptor Neprilysin Inhibitor (ARNi) and Sodium-glucose cotransporter-2 Inhibitor (SGLT2i) in Heart Failure Patients.

Introduction: Addressing access to life-saving therapy is crucial in influencing health outcomes. The stark reality of limited access to pharmacological therapy for heart failure with reduced ejection fraction (HFrEF), particularly novel drugs such as angiotensin receptor neprilysin inhibitors (ARNi) and sodium-glucose cotransporter-2 inhibitors (SGLT2i) for patients with heart failure (HF), underscores the challenges we face. Hypothesis: We analyze the impact of referring patients diagnosed with HF to our HF clinic by evaluating access to the 4 pillars of HFrEF, emphasizing cost-prohibiting pharmacological therapy, and assessing the efficacy of these medications when applied. Methods: This study compared 314 patients who live in counties within and outside the Penn State Health System. The data collected included healthcare insurance coverage, HF etiology, comorbidities, onset, initial and within six months post titration of guideline-directed medical therapy (GDMT) echocardiogram, and medication dose. Results: Among patients referred to our HF clinic, 184 live in counties within, and 130 live outside the Penn State Health System. The average age was 64, 69.4% were male, and a significant number of patients had HFrEF (92.7%). The prevailing comorbidities between the 2 groups were hypertension, hyperlipidemia, and diabetes. Upon completion, there was a significant increase in ARNi (83.1%) and SGLT2i (65.3%) use in both groups. They both (within vs. outside) reached almost similar percentages of triple therapy (77.9% vs. 79.2%; p-value=0.78), except for quadruple therapy (36.4% vs. 44.6%; p-value=0.16) and maximum tolerated dose (83.3% vs. 75%; p-value=0.11). The overall mean ejection fraction (EF) in both groups demonstrated significant improvement from pre-EF (30.5%) to post-EF (45.9%). Conclusion: Despite their location, patients referred to the HF clinic experienced intensified use of cost-prohibiting medications such as ARNi and SGLT2i, compared to the current gap in GDMT use. After optimizing GDMT, both groups had markedly improved EF. These findings suggest that referral to a HF clinic is a promising strategy for addressing the use of life-saving therapy and potentially reducing adverse health outcomes.

Abstract 4138553: Sodium-Glucose Cotransporter-2 Inhibitors After Acute Myocardial Infarction: A Meta-analysis of Randomized Controlled Trials

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) were initially developed to treat type 2 diabetes mellitus, but they have also shown benefits in mitigating cardiovascular risk. Given the increasing evidence of their efficacy in diverse disease states and their proposed mechanisms of action, it is plausible that SGLT2i could improve outcomes in patients with acute myocardial infarction (AMI) if administered early after presentation. However, the efficacy and safety of these therapies when used early in the course of acute coronary heart disease remain largely unexplored. Objective: The aim of this current study was to assess the benefit of early initiation of SGLT2i after AMI. Methods: We searched the Cochrane Central Registry of Controlled Trials, PubMed, Embase, Web of Science, and clinicalTrials.gov databases for all randomized controlled trials (RCTs) published up to May 2024 comparing SGLT2 inhibitors to placebo. The primary clinical endpoints included overall mortality, cardiovascular (CV) death, heart failure (HF) hospitalization, and adverse effects. Data were analyzed using a random-effects model to account for potential heterogeneity among the included studies. Significant heterogeneity was defined as an I-squared statistic ≥ 50%; a fixed-effects model was employed if heterogeneity was not significant. The odds ratio (OR) with a 95% confidence interval (CI) was calculated for each endpoint. Results: Four RCTs were included in the analysis, comprising 11,108 patients (SGLT2i, n = 5,561; placebo, n = 5,547) who enrolled with a mean age of 63±9 years and 77% males. SGLT2i were associated with a 28% reduction in risk of HF hospitalization (OR: 0.72 [95% CI, 0.59-0.88]; p = 0.001; I 2 = 0%). However, there was no significant reduction in overall mortality (OR: 1.01 [95% CI, 0.83-1.23]; p = 0.93; I 2 = 27%), CV mortality (OR: 1.04 [95% CI, 0.83-1.30]; p = 0.74; I 2 = 0%), and serious adverse effects (OR: 1.06 [95% CI, 0.87-1.28]; p = 0.59; I 2 = 62%). Conclusion: In patients with AMI, early initiation of SGLT2i was associated with a lower risk of HF hospitalization without increasing the incidence of serious adverse effects when compared to placebo. However, no significant difference was observed in overall mortality and CV deaths.

Abstract 4135582: Sociodemographic Trends in Diabetes Medications after Metformin: the BESTMED (oBservational Evaluation of Second line Therapy MEdications in Diabetes) Study

Objective: Though updated American Diabetes Association (ADA) guidelines recommend initiating GLP1 receptor agonists (GLP1) or SGLT2 inhibitors (SGLT2i) for persons with type 2 diabetes mellitus (PWT2DM) with high CV risk, metformin was previously recommended as 1st-line treatment. For PWT2DM at moderate CV risk, it is unknown which 2nd-line drug optimizes CV outcomes. Our multicenter observational study describes US-wide trends in 2nd-line T2DM medication use (DPP4 inhibitors [DPP4i], GLP1s, SGLT2i and sulfonylureas [SU]) overall and in key sociodemographic subgroups between 2014-2023. Methods: This is a secondary analysis of the oBservational Evaluation of Second line Therapy Medications in Diabetes (BESTMED) study, which used a new-user design to evaluate associations between 2nd-line medications and CV events in PWT2DM at moderate CV risk. The database comprised EHRs and insurance claims for 75,224 PWT2DM from 10 health systems and 2 insurance plans on metformin who initiated a 2nd medication from 1/2013 to 1/2023. Data were obtained from orders or prescription fills. Prescription class was regressed on calendar time via multinomial logistic regression to model trends in prescribing patterns, adjusted for sociodemographic variables. Subgroup analyses were performed by adjustment factors; CIs and p-values for differences were calculated via nonparametric bootstrap (B=200). Due to large sample size, statistical significance was interpreted at p<0.05 and annual rate of change >0.5%. Results: We included 75,224 T2DM adults (median A1c 7.8%), of whom 18%,17%, 18%, and 47% initiated DPP4i, GLP1, SGLT2i, SU respectively. From 2014 - 2023, SGLT2i and GLP1 increased: 5.7 to 28.8%, and 3.5 to 30.3%, and DPP4i and SUs decreased: 25.3 to 11.6%, and 65.6 to 29.3%, respectively. Annual rate of change for SGLT2i was higher in men(3.0% vs 2.1%/year; p<0.001) and in > 65 y (3.0% vs 2.4%; p<0.001), and for GLP1s was higher in those <65 y (3.6% vs 2.1%; p<0.001), women (3.5% vs 2.5%; p<0.001), Hispanic ethnicity (3.2% vs 2.7%; p=0.005), and with class II/III obesity (4.1% versus 2.6% per year; p<0.001). There was no evidence that these trends differed by race, insurance, or SDI. Conclusion: In this nationwide study of prescribing patterns PWT2DM at moderate CV risk, prevalences of 2nd-line T2DM therapies are approaching current ADA guidelines for initial therapy for those at high CV risk. Differences between sociodemographic groups appear aligned with clinical expectations.

The potential for improving cardio-renal outcomes in chronic kidney disease with the aldosterone synthase inhibitor vicadrostat (BI 690517): a rationale for the EASi-KIDNEY trial.

Patients with chronic kidney disease (CKD) are at risk of progressive loss of kidney function, heart failure, and cardiovascular death despite current proven therapies, including renin-angiotensin system inhibitors (RASi), sodium glucose co-transporter-2 inhibitors (SGLT2i), and statin-based regimens. RASi and SGLT2i reduce risk of CKD progression irrespective of primary cause of kidney disease, suggesting they target final common pathways. Targeting aldosterone overactivity with a nonsteroidal mineralocorticoid receptor antagonist (MRA) also reduces cardiorenal risk in patients with albuminuric diabetic kidney disease already treated with RASi. Together, these observations provide the rationale for trials to assess effects of inhibiting the aldosterone pathway in a broader range of patients with CKD, including those with non-diabetic causes of CKD or low albuminuria. Aldosterone synthase inhibitors (ASi) have emerged as an alternative to MRAs for aldosterone pathway inhibition. Phase II data from 586 patients with albuminuric CKD have shown that 10 mg of an ASi, vicadrostat (BI 690517), reduced urine albumin-to-creatinine ratio by ∼40% compared to placebo with or without concurrent empagliflozin treatment. MRA and ASi increase risk of hyperkalaemia. Combining their use with an SGLT2i may mitigate some of this risk, improving tolerability, and allowing a wider range of patients to be treated (including those with higher levels of blood potassium than in previous trials). The EASi-KIDNEY (NCT06531824) double-blind placebo-controlled trial will test this approach by assessing the safety and cardiorenal efficacy of vicadrostat in combination with empagliflozin in ∼11,000 patients with CKD. It will be sufficiently large to assess effects in patients with and without diabetes separately.

Abstract 4125157: Efficacy of Adding Sodium-Glucose Co-Transporter 2 Inhibitor versus Standard Therapy Alone in Post-Percutaneous Coronary Intervention Patients: A Systematic Review and Meta-Analysis

Background: Recent evidence suggests that sodium-glucose cotransporter-2 inhibitors (SGLT2-i) may improve outcomes in patients with coronary artery disease (CAD) through various physiological pathways. However, their impact on patients who have undergone percutaneous coronary intervention (PCI) is not well established. This meta-analysis aims to evaluate the effectiveness of additive SGLT2 inhibitors versus standard therapy alone in patients with CAD after PCI. Methods: A systematic search was conducted across the Medline, Embase, and Cochrane Library databases for randomized controlled trials (RCTs) and observational studies that compared the addition of SGLT2 inhibitors to standard therapy versus standard therapy alone in patients post-PCI. The outcomes analyzed were Major Adverse Cardiovascular Events (MACE), all-cause death, cardiovascular death, recurrent acute myocardial infarction (AMI), nonfatal stroke, revascularization, and hospitalization for heart failure (HF). Results: A total of 7 studies met the inclusion criteria, encompassing a total of 11,800 individuals (5,004 on SGLT2-i and 6,796 non-SGLT2-i; mean age of 62.7 years; 28% women; 95% diabetic patients). SGLT2 inhibitors significantly reduced the risk of all-cause mortality (RR 0.6, 95% CI: 0.5-0.72, p<0.01), cardiovascular death (RR 0.39, 95% CI: 0.16-0.94, p=0.03) and hospitalization for HF (RR 0.55, 95% CI: 0.4-0.76, p<0.01) compared to standard therapy alone. The occurrence of the composite endpoint (MACE) (RR 0.67, 95% CI: 0.44-1.01, p=0.056), any revascularization (RR 0.93, 95% CI: 0.57-1.53, p=0.784), recurrent AMI (RR 0.70, 95% CI: 0.41-1.18, p=0.176) and stroke (RR 0.94, 95% CI: 0.68-1.30, p=0.717) did not differ significantly between groups. Conclusions: Adding SGLT2 inhibitors to standard therapy significantly improved cardiovascular outcomes in patients with CAD who have undergone PCI, including reduced mortality and hospitalization for HF rates, with similar rates of recurrent AMI, coronary revascularization and stroke. These findings support the consideration of adding SGLT2 inhibitors as part of the therapeutic regimen for post-angioplasty patients, especially those with diabetes.

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.

Tofogliflozin reduces sleep apnea severity in patients with type 2 diabetes mellitus and heart failure: a prospective study.

Sleep apnea (SA) is prevalent among patients with heart failure (HF) and contributes to a poor prognosis. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated efficacy in reducing the risk of serious clinical events in patients with HF. Additionally, SGLT2 inhibitors may reduce the risk of incident SA and mitigate its severity in patients with cardiovascular disease and T2DM. We aimed to investigate whether the SGLT2 inhibitor tofogliflozin reduced the severity of SA, as assessed using the apnea-hypopnea index (AHI), in patients with HF and T2DM and whether a decrease in AHI correlates with changes in body composition and cardiorenal function parameters. This is a single-arm, prospective pathophysiologic study involving patients with HF, T2DM, and SA, defined as having an AHI of 15 events/h and more. SA was assessed using polysomnography. Changes in AHI before and 6 months after starting oral administration of tofogliflozin (20 mg) were assessed. Additionally, body composition and cardiorenal functions were assessed before and 6 months after tofogliflozin administration. Ten patients with HF, T2DM, and SA were finally enrolled (60% men, 66.9 ± 13.4 years). Tofogliflozin reduced AHI from 43.2 [30.2] to 35.3 [13.1] events/h (p = 0.024) at 6 months. Hemoglobin A1c, body weight, and body water content decreased significantly. However, no significant changes were observed in the cardiorenal function parameters. A linear relationship was observed between the changes in body water content and AHI (r = 0.642, p = 0.045). Tofogliflozin reduced AHI, possibly associated with a reduction in body water content.

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.