SGLT2 Research Articles

The Effects of SGLT2 Inhibitors on Blood Pressure and Other Cardiometabolic Risk Factors

Beyond their established hypoglycemic, cardioprotective, and nephroprotective properties, sodium–glucose cotransporters 2 (SGLT2) inhibitors exert other pleiotropic actions on blood pressure levels, body weight, and lipid metabolism. Blood pressure (BP) reduction varies based on the background history, including an effect on systolic, diastolic BP, and 24 h BP measurements. The reduction in body weight between 1 and 2 kg for the first months is caused by a reduction in visceral and subcutaneous fat due to glycosuria and loss of calories. Regarding lipid metabolism, a reduction in triglycerides and an increase in total cholesterol, high-density lipoprotein (HDL), and low-density lipoprotein (LDL) have been reported, although these alterations are small and could provide additional cardiovascular protection. Various pathophysiologic mechanisms have been proposed to explain the above-mentioned pleiotropic actions of SGLT2 inhibitors. Natriuresis, osmotic diuresis, body weight reduction, amelioration of endothelial dysfunction and arterial stiffness, sympathetic tone decrease, and uric acid reduction are among those that have been suggested for BP reduction. Apart from glycosuria and calorie loss, other mechanisms seem to contribute to body weight reduction, such as the beiging of white adipose tissue, while the mechanisms involved in lipid metabolism alterations have not been clearly determined.

Early Adoption of Sodium-Glucose Cotransporter-2 Inhibitor in Patients Hospitalized With Heart Failure With Mildly Reduced or Preserved Ejection Fraction

ImportanceSodium-glucose cotransporter-2 inhibitors (SGLT2is) are the first therapy shown to improve clinical outcomes for patients with heart failure (HF) and a left ventricular ejection fraction (LVEF) greater than 40%. Nationwide adoption of SGLT2is in the US since publication of the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved) in August 2021 is unknown.ObjectiveTo examine trends and hospital-level variation in SGLT2i adoption.Design, Setting, and ParticipantsThis cohort study included patients with LVEF greater than 40% who were hospitalized for decompensated HF at 1 of 557 sites in the US between July 1, 2021, and September 30, 2023, from the Get With The Guidelines–Heart Failure registry.Main Outcomes and MeasuresPatient-level trends and site-level variation in prescription rates of SGLT2i at hospital discharge. Site-level variation was quantified using the median odds ratio, which describes the average odds that a patient being treated at one vs another randomly selected hospital would receive SGLT2i therapy at discharge.ResultsOf 158 849 patients (median [IQR] age, 76 [66-85] years; 89 816 females [56.5%]), 22 126 eligible patients (13.9%) with HF and an LVEF greater than 40% were prescribed an SGLT2i at hospital discharge. Quarterly prescription rates increased from 4.2% in July to September 2021 to 23.5% in July to September 2023 (P for trend < .001). SGLT2i prescription was more likely among patients with HF with mildly reduced LVEF (41%-49%) than in those with preserved LVEF (≥50%; 5127 of 27 712 patients [18.5%] vs 16 999 of 131 137 patients [13.0%]; absolute standardized difference, 16.7%). After adjustment for patient characteristics, there was a high variance between hospitals in the rate of SGLT2i prescription (median odds ratio, 2.12; 95% CI, 2.02-2.25). Among 518 hospitals with 10 or more eligible discharges, 11 hospitals (2.1%) discharged 50% or more of their patients with an SGLT2i prescription, while 232 (44.8%) discharged fewer than 10% of eligible patients with an SGLT2i prescription.Conclusion and RelevanceFor patients with HF and an LVEF greater than 40%, discharge prescription of SGLT2is increased from 4.2% to 23.5% during the first 2 years after the EMPEROR-Preserved trial demonstrating treatment benefits; however, these rates varied across US hospitals.

Antidiabetic Medication and Asthma Attacks

ImportanceElevated body mass index (BMI) and type 2 diabetes are prevalent in asthma and are associated with an increase in the risk of asthma attacks. In experimental studies, the diabetes medications metformin and glucagon-like peptide-1 receptor agonists (GLP-1RA) have mitigated airway inflammation, hyperresponsiveness, and remodeling. However, epidemiological evidence is limited.ObjectiveTo estimate the association of metformin and add-on antidiabetic medications (GLP-1RA, dipeptidyl peptidase-4 inhibitors, sulphonylureas, sodium-glucose cotransporter-2 inhibitors, and insulin) with asthma attacks.Design, Setting, and ParticipantsThe study used data from the UK Clinical Practice Research Datalink (CPRD) Aurum linked hospital admissions and mortality data from 2004 to 2020. A triangulation approach was used that applied 2 distinct approaches to enhance robustness: a self-controlled case series (SCCS) and a metformin new user cohort with inverse probability of treatment weighting (IPTW). Eligible participants were new users of metformin with type 2 diabetes. To evaluate the association between metabolic phenotypes (BMI, glycemic control) and asthma phenotypes (type 2 inflammation, asthma severity), interaction analyses were conducted. Negative control analyses were conducted to assess for bias.ExposureThe primary exposure was metformin; secondary exposures included add-on antidiabetic medications.Main OutcomesThe primary outcome was first asthma exacerbation (short course of oral corticosteroids, unscheduled asthma-related hospital attendance, or death) during 12-month follow-up. Incidence rate ratios (IRRs) with 95% CIs were estimated using fixed-effect conditional Poisson models in the SCCS, and hazard ratios (HRs) were estimated using weighted Cox proportional hazards models in the cohort.ResultsOf more than 2 million adults with asthma, 4278 patients (2617 women [61.2%]; mean [SD] age, 52.9 [13.6] years) were identified for the SCCS and 8424 patients (4690 women [55.7%]; unexposed: mean [SD] age, 61.6 [13.2] years; exposed: mean [SD] age, 59.7 [13.7] years) for the IPTW cohort. Metformin was found to be associated with fewer asthma attacks of similar magnitude in both approaches (SCCS: IRR, 0.68; 95% CI, 0.62-0.75; IPTW: HR, 0.76; 95% CI, 0.67-0.85). Negative control analyses did not find evidence of significant bias. Hemoglobin A1c levels, BMI, blood eosinophil cell counts, and asthma severity did not modify the association. The only add-on antidiabetic medication to have an additive association was GLP-1RA (SCCS: IRR, 0.60; 95% CI, 0.49-0.73).Conclusions and RelevanceThe results of this cohort study suggest that metformin was associated with a lower rate of asthma attacks, with further reductions with the use of GLP-1RA. This appeared to be associated with mechanisms other than through glycemic control or weight loss and occurred across asthma phenotypes.

SGLT2 inhibitors increase low serum magnesium levels in patients with chronic kidney disease immediately after treatment.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors have been shown in clinical trials to increase serum Mg2+ levels in patients with type 2 diabetes mellitus. However, it is unclear whether this effect is similarly observed in patients with chronic kidney disease (CKD) and whether such an increase is observed immediately after treatment. Our retrospective observational study included the 62 patients with CKD who started SGLT2 inhibitor therapy at our institution between 2017 and 2022 and who had complete data on serum Mg2+ measurements at baseline and at 1, 3, and 6months after treatment. Patients were divided into three subgroups, stratified by serum Mg2+ levels at baseline. We evaluated the changes in serum Mg2+ levels from baseline to 6months after treatment and the factors associated with these changes. Median eGFR and mean serum Mg2+ at baseline were 33.5mL/min/1.73m2 and 2.03mg/dL, respectively. Treatment with SGLT2 inhibitors significantly increased serum Mg2+ levels immediately from 1month after treatment compared with those at baseline and persisted over 6months, with an overall mean change of 0.13mg/dL from baseline to 6months. This increased effect was observed in the low and middle tertile subgroups, but not in the high tertile subgroup. Multivariate linear regression analysis revealed that baseline serum Mg2+ levels and sodium-chloride differences, as a parameter of acid-base status, were independently associated with these changes. SGLT2 inhibitors increased serum Mg2+ levels in patients with CKD, particularly those with lower baseline Mg2+ levels, potentially improving their prognosis.

Updated evidence on cardiovascular and renal effects of GLP-1 receptor agonists and combination therapy with SGLT2 inhibitors and finerenone: a narrative review and perspectives.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have a reliable hypoglycaemic and weight-loss effect that can intervene in obesity, which is the basis of type 2 diabetes pathology. GLP-1RA therapy has shown potential benefits in reducing the risk of major adverse cardiovascular events and improving kidney outcomes in patients with diabetes at high risk for cardiovascular disease. More recent evidence is expanding their benefits to heart failure with preserved ejection fraction and clinically important renal outcomes in patients with and without diabetes. Some sub-analyses of large clinical trials suggest that GLP-1RA and sodium-glucose cotransporter 2 inhibitor combination therapy may provide more significant reductions in heart failure hospitalization and renal composite events than each alone. Moreover, the addition of finerenone to this combination therapy could potentially provide stronger cardiorenal protective benefits. Further studies are needed to assess the potential cardiovascular and renal benefits of combination therapy and to determine suitable patient population for the therapy.

Protective Potential of Sodium-Glucose Cotransporter 2 Inhibitors in Internal Medicine (Part 1)

Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a revolutionary class of drugs with far-reaching protective effects in multiple organs. The protective potential of SGLT2i is much broader than that of the classical concept of glucose control and consists of an entire conglomerate of associated pleiotropic effects. This study aims to provide a descriptive review of the pleiotropic therapeutic potential of SGLT2i. The first part of the literature review examined the use of SGLT2i in cardiology and nephrology. The use of SGLT2i represents an innovative approach to improving patients’ quality of life and course of heart failure and chronic kidney disease, regardless of left ventricular ejection fraction and type 2 diabetes.

SGLT 2 Inhibitors: Mechanisms, Clinical Applications, and Future Directions

Due to the progressive and painful nature of type 2 diabetes (T2D), treatment may require periodic evaluation of patients, intensifying glucose-lowering therapy when glycaemic targets are not achieved and testing new methods. Among the newer classes of glucose-lowering drugs, sodium-glucose cotransporter 2 inhibitors (SGLT2is), which increase urinary glucose excretion to reduce hyperglycaemia, have made an impressive entry into the T2D treatment arsenal. Given their unique insulin-independent mode of action and favourable efficacy-adverse effect profiles, and their apparent benefits on cardiovascular-renal outcomes in intermediate-high-risk T2D patients, which have led to the updating of guidelines and product monographs, the role of this drug class in multidrug regimens is promising. However, despite much speculation based on pharmacokinetic and pharmacodynamic properties, physiological rationale and potential synergism, the glycaemic and pleiotropic effects of these agents when combined with other classes of glucose-lowering drugs remain largely under-researched. Therefore, this review discusses the mechanisms, clinical applications and future therapeutic role of SGLT2 inhibitors with a review of the literature.

Insulin resistant diabetes mellitus in a girl with mild Rabson-Mendenhall syndrome: efficacy of sodium glucose co-transporter 2 inhibitor

Insulin resistant diabetes mellitus in a girl with mild Rabson-Mendenhall syndrome: efficacy of sodium glucose co-transporter 2 inhibitor

Determining optimal pretreatment in cardiac surgery: an experimental study.

Heart failure patients with reduced ejection fraction are currently treated with four drug combinations: angiotensin receptor/neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors, resulting in improved survival outcomes. Herein, we examined whether myocardial protection by esaxerenone or sacubitril/valsartan may present a counter-effect to the harm caused by cardioplegic arrest. Male Wistar rats fed a normal diet were orally administered esaxerenone (3mg/kg; Esax) or sacubitril/valsartan (68mg/kg; SaV) once a day for 2weeks from 6weeks of age. Age-matched, untreated male Wistar rats served as controls (Control). Isolated rat hearts were aerobically Langendorff-perfused and subjected to 2min of St Thomas' Hospital 2 cardioplegia (STH2) infusion and 28min of normothermic global ischemia followed by 60min of reperfusion. The recovery of function was measured during 60min of reperfusion. Additionally, troponin T levels were measured after reperfusion as myocardial injury. The final recovery of left ventricular developed pressure (presented as the percentage of preischemic value) in the Control, Esax, and SaV groups was 50.7 ± 6.2%, 68.5 ± 7.4%*, and 69.3 ± 14.3%*, respectively (*p < 0.05 vs. Control). Troponin T (ng per gram wet weight) levels in the Control, Esax, and SaV groups were 166.8 ± 78.1, 77.0 ± 14.6*, and 74.2 ± 36.6*, respectively (*p < 0.05 vs. Control). Oral administration of esaxerenone or sacubitril/valsartan to rats 2weeks prior to surgery enhanced the myocardial protection afforded by STH2 and may attenuate the myocardial injury caused by hyperkalemic cardioplegic arrest.

Rhabdomyolysis and Sodium-Glucose-Linked Transport Inhibitors in Patients Taking Statins.

This case-control study investigates the risk of rhabdomyolysis among patients receiving sodium-glucose cotransporter-2 (SGLT2) inhibitors.

The Incidence of Contrast-induced Acute Kidney Injury in Patients on Dapagliflozin Undergoing Percutaneous Coronary Interventions

Background: Sodium glucose cotransporter 2 receptor inhibitor (SGLT2i) dapagliflozin protects the renal function of individuals with coronary artery disease (CAD) and reduces incidence of contrast-induced acute kidney injury (CI-AKI) among individuals having percutaneous coronary interventions (PCI). The purpose of this work was to assess the CI-AKI incidence across individuals on dapagliflozin underwent PCI. Methods: This single-center, prospective observational work had been conducted on 200 diabetic individuals ranging in age between 25 and 80 years old, both genders, with CAD were going to have elective coronary angiogram and PCI. We identified CI-AKI by the ESUR and KDIGO definition. Patients were divided into two equal groups: Group I: Type 2 diabetes mellitus (T2DM) were on dapagliflozin (SGLT2i) and group II: T2DM were on non SGLT2i glucose-lowering drugs. Results: CI AKI according to European society of urogenital radiology (ESUR) and kidney disease improving global outcome score were significantly higher among group II contrasted to group I (P&lt;0.05). no significant correlations existed between contrast volume and creatinine post-PCI, estimated glomerular filtration rate (eGFR) post-PCI, high-density lipoprotein, total cholesterol, and hemoglobin A1c in both groups. Dapagliflozin use was significantly correlated with 76.2% risk reduction of AKI. Dapagliflozin usage had been correlated with a 72.6% risk reduction of AKI but with borderline significance (P = 0.064). eGFR post-PCI was significantly greater among group I cootrasted to group II (P &lt;0.05). Conclusions: Regarding the predictors of AKI according to ESUR criteria, multivariate logistic regression analysis and demonstrated that using dapagliflozin was substantially correlated with 76.2% risk reduction of AKI controlling for age, sex, hypertension, smoking, and dyslipidemia.

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 4129965: Efficacy of Sodium Glucose Cotransporter 2 Inhibitors In Patients With Acute Myocardial Infarction: A Meta-Analysis of Randomized Controlled Trials

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in patients with or without type 2 diabetes and heart failure (HF). However, studies have shown conflicting evidence regarding their efficacy in patients following acute myocardial infarction (MI). We conducted a systematic review and meta-analysis to synthesize the available evidence regarding the effectiveness of SGLT2 inhibitors in MI. Methods: A systematic literature search was conducted using PubMed/MEDLINE, the Cochrane Library, and Embase databases to identify randomized controlled trials (RCTs) that compared clinical outcomes of SGLT2 inhibitors with placebo following MI. We conducted the statistical analysis using RevMan, version 5.4, and pooled risk ratios (RRs) along the corresponding 95% confidence interval (CI) for all outcomes. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Results: Five RCTs reporting data for 11,211 patients were included in our study. Our pooled analysis showed that SGLT2 inhibitors significantly reduced the risk of hospitalizations for heart failure (HHF) (RR = 0.76, 95% CI: 0.61-0.88, p = 0.001; high certainty). In terms of absolute effects, this translated to 12 fewer HHF per 1,000 patients who received SGLT2 inhibitors compared with the placebo (absolute risk difference 12 (95% CI 17 to 5) fewer per 1000 patients) in patients with MI. However, the risk of all-cause mortality (RR = 1.05, 95% CI: 0.78-1.41, p = 0.76; high certainty), cardiovascular (CV) mortality (RR = 1.04, 95% CI = 0.84-1.29, p = 0.73; high certainty), and all-cause hospitalizations (RR = 1.06, 95% CI: 0.96-1.17, p = 0.25; high certainty) remained comparable across the two groups. Conclusion: SGLT2 inhibitors reduce HHF without affecting all-cause mortality, CV mortality, and all-cause hospitalizations. However, further evidence is required to reach a definitive conclusion.

Abstract 4121527: Empagliflozin Improves Mitochondrial Biogenesis in Pulmonary Arterial Hypertension

Background: Pulmonary arterial hypertension (PAH) is a devastating disease characterized by endothelial proliferation and progressive pulmonary vascular (PV) remodeling. Empagliflozin (EMPA), a sodium glucose cotransporter 2 (SGLT2) inhibitor, benefits heart failure patients, potentially mediated by improved mitochondrial function. This study aimed to explore the impact of EMPA in PAH. Methods and Results: Immunohistochemistry of pulmonary arteries revealed the expression of SGLT2 in the intima of PAH patients. Microvascular endothelial cells (MVECs) were isolated from lungs of control subjects (CTRL) and PAH patients and found intense expression of SGLT2 in PAH MVECs. Western blot showed significantly higher expression of SGLT2, while PGC-1α, a transcriptional coactivator known as a master regulator of mitochondrial biogenesis, was lower in PAH MVECs compared to CTRL (Image 1). PAH MVECs were treated with EMPA (1 μM) and observed a significant increase of PGC-1α and BMPR2-pSmad1/5/9. Similarly, knockdown of SGLT2 using siRNA resulted in enhanced expression of PGC-1α. Moreover, Seahorse analysis revealed increased oxygen consumption rate and reduced extracellular acidification rate by EMPA, suggesting that EMPA improved mitochondrial respiration. In addition, EMPA attenuated reactive oxygen species and proliferation of PAH MVECs, as revealed by MitoTracker analysis and MTT assay respectively. For the in vivo study, Sprague-Dawley rats (120-180 gram) were injected with SU5416 (Week-0) and exposed to hypoxia for 3 weeks followed by normoxia. After randomization at Week-4, rats were treated with EMPA (300 mg/kg in chow, n=12) or placebo (PLAC, n=12). Catheterization and histological analysis were performed at Week-8. EMPA decreased PV resistance index (0.21±0.02 vs. 0.37±0.05 mmHg/mL/min/mm 2 , p=0.01), ameliorated intima thickening (21.0±7.5 vs. 40.0±7.8%, p&lt;0.01) and vessel occlusion (Image 2). We further conducted a single-center, open-label, single-arm interventional proof-of-concept study to assess the tolerability of 12 weeks of treatment with 10mg of EMPA as add-on therapy in eight patients with a prior PAH diagnosis. There were no treatment related adverse events during the study time course. Conclusions: EMPA directly improved mitochondrial biogenesis and attenuated proliferation of MVECs from PAH patients and reversed PV remodeling in experimental PAH. EMPA treatment was feasible in patients with PAH. EMPA may serve as a new therapeutic option for PAH.

Abstract 4136969: Empagliflozin's Role in Post-Myocardial Infarction Management: Insights from a Meta-Analysis

Background: Empagliflozin, a Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor, is used to treat type 2 diabetes mellitus and heart failure. Its safety and efficacy in patients with Myocardial Infarction (MI) have been studied recently. Research Questions/Hypothesis: What is the role of Empagliflozin in post-myocardial infarction management by preventing cardiovascular deaths, reducing hospitalization due to heart failure, and minimizing adverse events? Goals/Aims: Role of Empagliflozin in post-myocardial infarction management by preventing cardiovascular deaths, reducing hospitalization due to heart failure, and minimizing adverse events Methods: A literature search was done on PubMed, Medline, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials from inception until May 2024. All Randomized Control Trials (RCT) reporting the safety and efficacy of Empagliflozin in MI management were selected. Outcomes were pooled as Mean Difference (MD) or Risk Ratio (RR) with 95% Confidence Intervals (CI) in this meta-analysis using Revman 5.4. Results: Data from ten RCTs, with a combined sample size of 10,560 patients was pooled, and showed that Empagliflozin is superior to placebo in terms of Cardiovascular death (RR=0.75, 95% CI [0.64, 0.88],p &lt; 0.0004) and hospitalization due to heart failure (RR=0.70, 95% CI [0.59, 0.82], p &lt; 0.0001). However, the results were non-significant for both groups in terms of adverse events (RR=1.00, 95% CI [0.96, 1.03], p &lt; 0.78). Conclusion: Empagliflozin significantly lowers the risk of cardiovascular events in patients with MI who are at a high risk of death due to cardiovascular causes.

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 4121215: Efficacy and Safety of Empagliflozin in Patients with Acute Myocardial Infarction: A meta-analysis of randomized controlled trials

Background: Empagliflozin is a sodium glucose co-transporter 2 inhibitor that improves cardiovascular outcomes in patients with type 2 diabetes mellitus, chronic kidney disease and heart failure. Less is known about the efficacy and safety of empagliflozin in patients after acute myocardial infarction. Methods: PubMed, Embase and Cochrane databases were searched for randomized controlled trials (RCTs) that reported the outcomes of interets including all-cause mortality, death from cardiovascular causes, hospitalization due to heart failure etc. Risks ratios (RR) or mean difference (MD) and their 95% confidence intervals (CIs) were computed with the use of random-effect model. Heterogeneity was examined with I 2 statistics. Results: We included 12 RCT articles consisting of 23,178 patients that received empagliflozin after acute myocardial infarction were considered. Empagliflozin was associated with significantly reduced incidence of all-cause mortality (RR 0.72; 95% CI [0.61, 0.85]; P &lt; 0.0001; 5.9% vs 7.4%), death from cardiovascular causes (RR 0.66; 95% CI [0.52, 0.83]; P = 0.0004; 4.0% vs 5.4%), and hospitalization for heart failure (RR 0.66; 95% CI [0.58, 0.76]; P &lt; 0.00001; 3.2% vs 4.7%), acute kidney injury (RR 0.52; 95% CI [0.31, 0.86]; P = 0.01), acute renal failure (RR 0.71; 95% CI [0.55, 0.91]; P = 0.008), adverse events leading to discontinuation (RR 0.89; 95% CI [0.80, 0.99]; P = 0.03), systolic blood pressure (MD -8.59; 95% CI [-13.26, -3.93], P = 0.0003), and thromboembolic events (RR 0.51; 95% CI [0.28, 0.92]; P = 0.03) compared to placebo. However, there was no significant difference between groups with respect to fatal or nonfatal stroke (RR 1.15; 95% CI [0.91, 1.46]; P = 0.23), adverse events leading to lower limb amputation (RR 1.11; 95% CI [0.62, 1.99]; P = 0.73), estimated glomerular filtration rate (MD 0.45; 95% CI [-0.20, 1.10]; P = 0.17), diastolic blood pressure (MD -2.53; 95% CI [-5.40, 0.34]; P = 0.08), body weight (MD -1.04; 95% CI [-4.08, 1.99]; P = 0.50), urinary tract infection (MD 1.04; 95% CI [0.92, 1.17]; P = 0.55), NT- proBNP (MD -115.93; 95% CI [-271.52, 39.66]; P = 0.14), glycated hemoglobin (MD -0.10; 95% CI [-0.41, 0.22]; P = 0.55), and hypoglycemia (RR 0.98; 95% CI [0.89, 1.08]; P = 0.70). Conclusion: Our findings suggest that empagliflozin has superior efficacy and safety compared to placebo for the treatment of patients with acute myocardial infarction with no impact on UTI, eGFR, NT-proBNP, and hypoglycemia.

Abstract 4134267: Effects of GLP-1 Receptor Agonists and SGLT2 Inhibitors on In-Hospital Mortality and 30-Day Readmission in Type 2 Diabetic Patients with Acute Coronary Syndrome

Background: The effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium–glucose cotransporter 2 inhibitors (SGLT2is) on reducing cardiovascular events in heart failure patients are well-established; however, less is known about their effects after a myocardial infarction. This study aims to investigate the effects of GLP-1RAs and SGLT2is on in-hospital mortality and 30-day readmission in type 2 diabetic patients with/without heart failure who were hospitalized for acute coronary syndrome (ACS). Methods: We conducted a multicenter retrospective cohort on type 2 diabetic patients who were admitted to the hospital for ACS from 01/01/2020 to 01/31/2024 across 16 West Florida hospitals. Patients receiving a GLP-1RA alone, SGLT2i alone, or both were compared to those taking neither. Chi-square and binary logistic regression were used to predict the clinical outcomes of in-hospital mortality, all-cause readmission within 30 days, and cardiac readmission within 30 days. Results: Among 7,481 type 2 diabetics with ACS, 392 (5.24%) were taking GLP-1RA monotherapy, 577 (7.71%) were taking SGLT2i monotherapy, 144 (1.92%) were taking both, and 6,362 (85.12%) were taking neither. The likelihood of in-hospital mortality was similar among patients on neither medication compared to patients on both (χ 2 = 0.06, p = 0.802), GLP-1RA monotherapy (χ 2 = 0.61, p = 0.435), and SGLT2i monotherapy (χ 2 = 0.002, p = 0.968). The odds of all-cause readmission within 30 days was similar among patients on neither medication compared to patients on both (χ 2 = 0.0004, p = 0.983), GLP-1RAs monotherapy (χ 2 = 0.07, p = 0.791), and SGLT2i monotherapy (χ 2 = 3.10, p = 0.078). The likelihood of cardiac readmission within 30 days was similar among patients on neither medication compared to patients on both medications (χ 2 = 1.63, p = 0.202), GLP-1RA monotherapy (χ 2 = 0.95, p = 0.329), and SGLT2i monotherapy (χ 2 = 0.94, p = 0.332). Conclusion: Our study found no significant differences in the odds of in-hospital mortality or 30-day readmission among type 2 diabetics with ACS who were taking GLP-1RAs, SGLT2is, or both, when compared to those taking neither. These findings further support the outcomes discovered in the EMPACT-MI trial.

Abstract 4120515: Impact of 2022 AHA/ACC/HFSA Heart Failure Guideline Value Statement Publication on Medicare Drug Coverage Policies

Background: Patients with heart failure (HF) often have difficulty obtaining life-saving medications due to coverage barriers, such as prior authorizations (PA) and high out of pocket (OOP) costs. To promote better insurance coverage of high value therapies, the AHA/ACC/HFSA added Value Statements to HF guidelines to inform policymakers about medication cost effectiveness. We assessed whether these guidelines influenced Medicare drug coverage policies for two life-saving, costly HF medications: angiotensin receptor neprilysin inhibitors (ARNI – guideline “high value”) and sodium glucose cotransporter 2 inhibitors (SGLT2i – guideline “intermediate value”). Methods: We performed an observational study of Medicare drug plans from 4/2020-4/2023 to assess for changes in ARNI and SGLT2i coverage after Value Statement publication (4/2022), and subsequent Medicare plan online update (10/2022). The primary outcome was any barrier to drug coverage (PA, tier ≥ 3 OOP cost-sharing, step therapy, or no coverage). Analysis utilized interrupted time series and difference-in-difference (DiD) approaches. DiD analyses used direct oral anticoagulants as a control due to similar cost and utilization as ARNI and SGLT2i, but with no Value Statement. Results: Among 7,396 Medicare drug plans, 94.3%-97.4% had coverage barriers to ARNI and 93.2%-96.6% to SGLT2i. The majority of barriers were due to tier ≥ 3 OOP cost-sharing requirements (ARNI: 94.3%-95.8%; SGLT2i: 93.2%-95.6%). Coverage barriers remained stable in 4/2022, and declined slightly in 10/2022 (Figure). In DiD analyses, the presence of a Value Statement was associated with a ~1 percentage point decline in coverage barriers for ARNI and SGLT2i. Conclusion: Coverage barriers to ARNI and SGLT2i were common and did not change much in response to Value Statements in HF Guidelines. Increased consideration for Value Statements by Medicare policy-makers is needed to meaningfully improve access to high value therapies.