SGLT2 Research Articles

Presence of Atrial Fibrillation (AF) is a poor prognostic marker in patients with Heart Failure with reduced Ejection Fraction (HFrEF) and Left Bundle Branch Block (LBBB)

Abstract Background Observational data indicate that between 20-30% of patients with HFrEF have LBBB. While numerous independent variables are implicated in the overall prognosis of these patients, this group of patients respond poorly to medical therapy. Presence of AF further impairs the functioning of the left ventricle by several mechanisms e.g., left atrial dilatation, decreased left ventricular filling, irregular cycle length, functional mitral regurgitation etc. Literature is sparse on the cumulative effect of AF in this group of patients. Purpose To assess the effect of AF on left ventricular ejection fraction (LVEF) and mortality in patients presenting with HFrEF and LBBB Methods Single centre, retrospective, observational study over 33 months (Jan 2021 – Sept 2023). Patients with HFrEF and LBBB (as defined by the European Society of Cardiology, 2021) identified from the heart failure database. Results (Table) N=80 Whole cohort: age 74.8 +/- 13.6 years (median:79, range 39-96); 57/80 (67.5%) males. Hypertension [41/80 (51.3%)] was most common comorbidity. Majority were on 3 drugs (23/80, 28.8%) of guideline directed medical therapy (GDMT) with ~1 in 4 patients [19/80 (23.8%)] on all 4 drugs. 32/80 (40.0%) were in AF, remainder in sinus rhythm (SR). Mean baseline LVEF: 21.8 +/- 8.4. Mean LVEF continued to be ≤35% (paired echocardiograms available in 50.0% patients) inspite of GDMT. The QRS duration continued to prolong on follow-up. Patients in AF were statistically significantly older, were less often on all 4 GDMT drugs (particularly sodium glucose transporter 2 inhibitors - SGLT2i’s), and were less likely to survive than those in SR. No difference in comorbid conditions or QRS prolongation on follow-up were seen between patients with AF versus SR. There was trend towards a larger increase in mean LVEF in patients with SR than AF. Conclusions In our experience, patients with HFrEF and LBBB continue to have a high mortality (45.0% at ~ 3 years) inspite of GDMT. AF is seen in a high percentage of patients (40.0%) in this cohort, worsening the prognosis further, with mortality nearly 3 times higher than those in SR. Aggressive management of patients with HFrEF and LBBB with, where indicated, early cardiac resynchronisation therapy (CRT) and more so, of those with AF (with +/- atrioventricular node ablation or left atrial ablation) should be considered at an early stage after diagnosis.Table

Comparison of ventricular tachyarrhythmias in HF patients on dapagliflozin versus empagliflozin

Abstract Background Ventricular tachycardia (VT) and ventricular fibrillation (VF) are devastating tachyarrhythmias that can cause sudden cardiac death in patients with heart failure (HF) if not anticipated or treated promptly. Although post-hoc analysis in DAPA-HF showed promise in their benefit, Sodium-glucose transport protein 2 inhibitors (SGLT2i) have not yet been evaluated for their effect on these tachyarrhythmias. This retrospective analysis aims to compare the 2 most commonly used SGLT2i agents, dapagliflozin and empagliflozin, and the incidence of VT in patients with HF. Methods The TriNetX Research network was used for this study. The two initial patient cohorts were created using ICD-10 codes and medication codes from the TriNetX platform. Both cohorts consisted of patients over age 60 with a history of heart failure and either VF or VT. One cohort was on treatment with dapagliflozin and the other with empagliflozin. The cohorts were balanced by propensity score matching and the greedy nearest neighbor algorithm for age, gender, race, ethnicity, hyperkalemia, and the current use of spironolactone, amiodarone, metoprolol, and carvedilol, resulting in 9,841 patients in each arm. The cohorts were then evaluated for the development of VF or VT over the subsequent five years as well as all-cause mortality. Additional cohorts were created to evaluate dapagliflozin vs empagliflozin in diabetics, nondiabetics, and patients with ejection fractions less than 35% Results Dapagliflozin was associated with an increased risk of ventricular arrhythmia in heart failure patients compared to empagliflozin (46.0% vs. 40.8%, RR 1.13, 95% CI (1.09,1.16), P value < 0.0001). It was also associated with higher mortality at five years (RR 1.10, 95% CI (1.03,1.18), P value 0.0034). Conclusions In comparisons between dapagliflozin and empagliflozin in heart failure patients with previously documented ventricular arrhythmias, empagliflozin had 13% less risk of recurrence of ventricular arrhythmias. Secondarily, the empagliflozin cohort also exhibited lower all-cause mortality (14.8% vs 16.3%) at five years from starting the drug. Our analysis does not disprove findings in DAPA-HF, but rather may support the potential class effect of SGLT2 inhibitors in their ability to suppress VT.(1) Importantly, the overall incidence of ventricular tachyarrhythmias is high in both cohort, given we selected a high-risk population. Notably, our documented recurrence rate is similar to past reports of recurrence after VT ablation, the gold standard for treatment of VT. (2) SGLT2 inhibitors have shown clear benefit in multiple placebo-controlled studies in terms of heart failure outcomes like mortality and readmission, but their effect on arrhythmias is one more additional benefit this class may have. (3) Given these associations, empagliflozin may be a more favorable options for HF patients who have already had VT or VF.

Dapagliflozin versus empagliflozin and major adverse cardiovascular events in type 2 diabetes: a nationwide cohort study

Abstract Background Large randomized clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure, chronic kidney disease, or type 2 diabetes mellitus (T2DM) at high risk of atherosclerotic cardiovascular disease. Whether these effects might differ between individual SGLT2-inhbitors remain unclear given the lack of head-to-head comparisons. Purpose To examine the association between treatment with dapagliflozin versus empagliflozin and the long-term rate of major adverse cardiovascular events (MACE) in patients with T2DM. Methods Using nationwide registries, all Danish residents with T2DM, who initiated treatment with dapagliflozin or empagliflozin from 2015 to 2020, were identified. Only treatment with dapagliflozin or empagliflozin was considered in the present analysis, since approximately 3% initiated treatment with other SGLT2-inhibitors (i.e., canagliflozin and ertugliflozin). Patients were followed from date of the first claimed prescription of dapagliflozin or empagliflozin until the outcome of interest, emigration, death, or end of study (December 31, 2021). The primary outcome was a composite endpoint of major adverse cardiovascular events (i.e., time to first heart failure hospitalisation, acute myocardial infarction (AMI), stroke, or all-cause mortality). The primary outcome was compared between the dapagliflozin and empagliflozin group, overall and in prespecified subgroups of interest, with multivariable Cox proportional hazards regression models. Results In total, 61,031 patients with T2DM initiated treatment with dapagliflozin (N=21,028; 34.5%) or empagliflozin (N=40,003; 65.5%). The median age of study population was 62.6 years (25th-75th percentile, 54.2-70.8 years), and 62.6% were men. There were no clinically significant differences between the dapagliflozin and empagliflozin group with respect to age, sex, and clinical characteristics. The median follow-up was 3.1 years (25th-75th percentile, 1.9-4.5 years). The adjusted long-term hazard ratios of the primary outcome, overall and in prespecified subgroups of interest, are displayed in the Figure. Compared with empagliflozin, treatment with dapagliflozin was not associated with a significantly different rate of the primary outcome (HR 1.02 [95% CI, 0.97-1.07]). The observed association was consistent across clinically relevant subgroups, including in patients with and without heart failure, chronic kidney disease, and atherosclerotic cardiovascular disease. Conclusion In a large, nationwide cohort of patients with T2DM, treatment with dapagliflozin was associated with a similar rate of major adverse cardiovascular outcomes compared with empagliflozin, and this association was consistent across clinically relevant subgroups. These findings suggest that the benefits of SGLT2-inhibitors can be characterized as a class-effect.

Implementation of sodium-glucose co-transporter 2 inhibitors in patients with heart failure through a new digital strategy (EMAIL-HF): a randomised clinical trial study design

Abstract Introduction Delayed implementation of new medical discoveries remains a global healthcare challenge and is mainly due to the complexity of cross-institutional patient care. Sodium-glucose co-transporter-2 (SGLT-2) inhibitors is the latest medical discovery in heart failure (HF) and have recently been added to clinical guidelines as they have proven to reduce the risk of adverse cardiovascular outcomes in patients with HF across the ejection fraction spectrum. Whether a new digital strategy can optimise and accelerate the implementation of SGLT2 inhibitors in patients living with HF is of great importance for public health. Purpose To evaluate whether a new and streamlined digital strategy can optimise and accelerate the implementation of SGLT2 inhibitors in patients with HF. Design and methods: The trial is a multicentre, parallel group, register-based randomised clinical study, evaluating the effect and potential of a new digital strategy to implement new guideline therapies to patients living with a chronic disease, specifically SGLT2 inhibitors to patients with HF (figure 1). The setup employs data from nationwide health registers and official digital letters to inform patients about the new therapy option and invite them to have their eligibility evaluated by a HF specialist and start therapy. A total of ~10,000 patients with HF across the ejection fraction spectrum (with and without diabetes), who have not yet been started on SGLT2 inhibitors, are identified through Danish nationwide health registers, and randomised 1:1 to receive the digital letter (figure 2). The primary outcome is the proportion of patients redeeming a prescription of a SGLT2 inhibitor within six months. Secondary outcome is a composite HF endpoint consisting of all-cause death or HF hospitalisation. Other outcome measures are renal failure, stroke and myocardial infarction, safety outcomes, adherence to therapy and proportion of vulnerable patient groups initiating therapy including immigrants, elderly, frail patients, patients with lower socioeconomic level and lower educational level. A total of 4689 patients have been randomised (February 2024) and data will be presented in 2025. Conclusions The trial will determine the efficacy and safety of a new and streamlined digital strategy to implement SGLT2 inhibitors to patients with chronic HF. The setup has the potential to be used in a broad spectrum of patients living with chronic diseases and is expected to be highly cost-effective.Figure 1.Study hypothesisFigure 2.Study design

SGLT2 inhibitors are associated with development of heart failure with improved ejection fraction

Abstract Background Heart failure (HF) with improved ejection fraction (EF), termed HFimpEF, has been proposed as a new HF classification associated with better clinical outcomes. Sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce cardiovascular death and hospitalization for HF irrespective of diabetes. Purpose Analyze the effect of SGLT2 inhibitors on the development of HFimpEF. Methods Consecutive HF with reduced EF (HFrEF) patients with follow-up echocardiogram at around 12 months were enrolled from 2017 to 2022. Patients were classified into HFimpEF (follow-up EF > 40% and ≥ 10% absolute increase) or otherwise persistent HFrEF based on repeat echocardiograms after 12 months. A 1:2 propensity score matched analysis was performed. Results Of all the HFrEF patients in the cohort, 46.6% of patients developed HFimpEF. We matched 93 and 186 patients treated with or without SGLT2 inhibitors according to propensity score. In the matched cohort, treatment with SGLT2 inhibitors was associated with nearly a doubled likelihood of the development of HFimpEF (OR: 1.978 [95% CI 1.184~3.346]). Subgroup analysis revealed this association was only present in HF patients with an ischemic etiology (OR: 3.427 [95% CI 1.614~7.573], P for interaction=0.022). There was no significant interaction term between SGLT2 inhibitors and the presence of diabetes for the development of HFimpEF. Conclusions This study reveals that treatment with SGLT2 inhibitors is associated with increased likelihood of HFimpEF, especially in those with an ischemic etiology.

Comparative outcomes between empagliflozin and dapagliflozin in heart failure: real world multi-center cohort study

Abstract Introduction Heart failure (HF) is a significant global health concern, and sodium-glucose cotransporter-2 (SGLT2) inhibitors, such as dapagliflozin and empagliflozin, have emerged as important therapeutic options. However, their comparative effectiveness in a real-world population remains uncertain. Purpose The purpose of this multicenter, population-based cohort study was to investigate and compare the outcomes associated with dapagliflozin and empagliflozin use in patients with heart failure. We sought to understand whether these SGLT2 inhibitors had differential effects on cardiovascular events in a real-world setting. Methods We analysed data from a clinical data warehouse encompassing seven medical centers. Subjects diagnosed with heart failure between January 2021 and November 2023, who were prescribed dapagliflozin or empagliflozin, were included. We conducted one-to-one propensity-score matching, ensuring that the dapagliflozin and empagliflozin groups were comparable in baseline characteristics. The primary outcome was a composite of cardiovascular (CV) death or hospitalization for HF, analysed as the first event occurring after starting each medication. Secondary outcomes included individual components, all-cause death, and CV hospitalization. Results Propensity-score matching made a balanced cohort of 6,281 patients (3,111 in the dapagliflozin group and 3,170 in the empagliflozin group). The median follow-up duration was 16.0 months. In the propensity-score matched cohort, dapagliflozin and empagliflozin showed no significant difference in the primary outcome (8.8% versus 7.8%, hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.77-1.08, p=0.276). Similar findings were observed in secondary outcomes. Subgroup analysis revealed potential benefits of empagliflozin in patients with diabetes mellitus (DM) (7.8% versus 5.6%, HR 0.73, 95% CI 0.55-0.98, p=0.039). Conclusion This study suggests that dapagliflozin and empagliflozin have similar clinical outcomes in the management of heart failure in a real-world setting. However, empagliflozin showed result in improving outcomes for HF patients with DM. Further research is warranted to validate these findings and guide clinical decision-making in the individualized management of heart failure.Baseline characteristicsSubgroup analysis

Activation of fibroblast growth factor 21 by Canagliflozin reduces high-fat diet associated obesity-related cardiac injury: a translational study from bench to bedside

Abstract Aims/hypothesis Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are indicated for the treatment of type 2 diabetes, and evidence shows that they may confer a cardioprotective effect to reduce the incidence of cardiovascular conditions in obese type 2 diabetes patients. The mechanisms underlying this effect remain unclear, but an SGLT2i, canagliflozin (CANA), has been reported to increase levels of fibroblast growth factor-21 (FGF21) and enhance activation of its downstream target proteins. We thus aimed to study whether the effect on FGF21 by CANA can reduce obesity-related cardiac injury. Methods 1) Animal study: Sixteen-week-old normal diet and high-fat diet male mice were treated with or without 30 mg/kg CANA once a day for 24 weeks, and were subsequently examined for body weight, blood glucose levels, adipose tissue changes, lipid accumulation in the liver, and cardiac function. 2) Cell study: An in vitro study that treated H9c2 cardiomyocyte cells cultured in a simulated high-lipid environment containing palmitic acid (PA) with FGF21 recombinant protein was also conducted to examine protein expression profiles. Furthermore, the effect of CANA on FGF21 expression. 3) Human clinical trial: A randomized double-blinded control trial (NCT 05764811) was performed to test effect of CANA on MRI liver fibrosis scores of obese type 2 diabetes patients (n = 40). Results 1) High-fat diet mice treated with CANA for 24 weeks had lower average body weight than untreated controls (34 g vs. 40 g, p < 0.001). In addition, CANA treatment stimulated FGF21 protein production in liver tissue and plasma at higher levels for both normal diet and high-fat diet mice, and reduced expression levels of proteins associated with fibrosis and apoptosis. 2) H9c2 cardiomyocyte culture studies suggested that a simulated high-lipid environment with PA caused higher expression of apoptotic proteins, but the addition of FGF21 recombinant protein significantly reduced apoptosis signalling. 3) MRI before and after 4 weeks of CANA treatment in obese type 2 diabetes patients showed a significant reduction in liver fibrosis scores for those receiving CANA treatment. Conclusion CANA treatment stimulated FGF21 protein expression and reduced fibrosis and apoptosis signalling protein expression. Moreover, reductions in liver fibrosis scores were observed in obese type 2 diabetes patients treated with CANA. Taken together, this suggests that CANA-induced FGF21 expression may exert a cardioprotective effect against fibrosis and apoptosis and can potentially reduce the risk of obesity-related cardiac injury.

Comparative analysis of renin-angiotensin system inhibitors/angiotensin receptor neprilysin inhibitor and mineralocorticoid receptor antagonists in heart failure with mildly reduced ejection fraction

Abstract Background Apart from sodium-glucose co-transporter 2 inhibitors, the efficacy of renin–angiotensin system inhibitors/angiotensin receptor neprilysin inhibitors (RASI/ARNI)j8788 as well as mineralocorticoid receptor antagonist (MRA) in patients with heart failure with mildly reduced ejection fraction remains uncertain. We assessed the association between these medications and outcomes in patients with heart failure with mildly reduced ejection fraction (HFmrEF). Methods Patients with HFmrEF from our university hospital-integrated Medical Database were included. Associations between the medications and cardiovascular mortality/heart failure hospitalization were evaluated using Cox regressions in a 1:1 propensity score-matched cohort. Inverse probability of treatment weighting was employed to balance baseline patient characteristics. Results Of 2584 patients with HFmrEF, 17% received MRA and 43% received RASI/ARNI. Predictors of MRA use included older age, slightly higher ejection fraction, lower NT-proBNP level, and eGFR >60 mL/min/1.73 m^2. Predictors of RASI/ARNI use included higher body mass index, lower NT-proBNP level, normal uric acid level, normal potassium level, and eGFR >60 mL/min/1.73 m^2. MRA use was not associated with a lower risk of cardiovascular death and hospitalization for heart failure (hazard ratio [HR] = 0.89, 95% confidence interval [CI]: 0.78–1.02 and HR = 1.01, 95% CI: 0.94–1.09, respectively). Conversely, RASI/ARNI use was associated with a lower risk of cardiovascular death but not hospitalization for heart failure (HR = 0.82, 95% CI: 0.71–0.94 and HR = 0.995, 95% CI: 0.924–1.07, respectively). Notably, landmark analysis revealed no significant difference in the risk of outcomes when the follow-up duration exceeded two years. Conclusions The effect of MRA on cardiovascular death and hospitalization for heart failure was neutral, whereas RASI/ARNI was associated with a lower risk of cardiovascular death. Our findings suggest that RASi use may be more beneficial than MRA use in patients with HFmrEF.

Randomized trial assessing worsening renal function with dapagliflozin addition in acute decompensated heart failure: ROAD-ADHF trial

Abstract Background Dapagliflozin (DAPA), a sodium-glucose co-transporter 2 inhibitor, has shown to reduce cardiovascular mortality in patients with chronic heart failure.1) In addition, DAPA can enhance diuresis in patients with acute decompensated heart failure (ADHF).2) However, there is little known how early initiation of DAPA might impact the worsening renal function (WRF) when combined with standard decongestive therapy for ADHF. Purpose We aimed to evaluate the impact of initiating DAPA within 24 hours after ADHF admission on WRF, compared to standard decongestive therapy with loop diuretics alone. Methods We enrolled consecutive ADHF patients with a left ventricular ejection fraction (LVEF) less than 50%. The patients were prospectively randomized to either the DAPA group who received DAPA at a dose of 10 mg once daily within 24 hours of admission or the conventional therapy group (CON group) who received loop diuretics alone. Furosemide, loop diuretic, dosage was adjusted by increase or decrease of 10 mg to maintain urine output between a 1-2 mL/kg/hour.3) The primary endpoint was the incidence of WRF, which was defined as an increase in the serum creatinine of ≥ 0.3 mg/dL from baseline within 7 days of admission.4) Additionally, right heart catheterization (RHC) was performed before discharge if the consent was obtained. Results From May 2021 to May 2023, we analyzed a total of 114 patients (56 in the DAPA group and 58 in the CON group). The mean age was 73 years, 35% were female, and the mean LVEF was 32.5%. There was no significant difference in the incidence of WRF between two groups (16.1% in the DAPA group vs. 12.1% in the CON group, P=0.54, Figure 1). The cumulative loop diuretics dose over 7 days was lower in the DAPA group than CON group (184 ± 9.64 mg vs. 214 ± 9.81 mg, P=0.03, Figure 2). RHC before discharge was performed in 54 patients (96.4%) in the DAPA group and in 54 (93.1%) in the CON group. There were no significant differences in the pulmonary artery wedge pressure, pulmonary artery pressure, right atrial pressure, and cardiac index by the thermodilution method or the Fick method between two groups. Conclusion This randomized prospective trial revealed the early initiation of DAPA within 24 hours of admission for ADHF reduced loop diuretic demand without inducing WRF compared to standard decongestive therapy.Figure 1Figure 2

Safety and effectiveness of sodium-glucose co-transporter 2 inhibitors in active cancer patients with heart failure: results of the observational TOSCA trial

Abstract Background Sodium-glucose co-transporter 2 inhibitors (SGLT2i) currently represent a pillar of heart failure (HF) treatment. However, cancer patients have not been included in landmark randomized controlled trials (RCTs), and data on safety and effectiveness in this population are lacking. Purpose Purpose of present study was to evaluate safety and effectiveness of SGLT2i in active cancer patients with HF. Methods TOSCA is a multi-centre observational trial including patients (≥ 18 years) with active cancer (diagnosis < 3 years) receiving SGLT2i for HF treatment. Patients were enrolled in two (prospective and retrospective) cohorts. The primary endpoint was safety (incidence of known and unexpected side effects). The secondary endpoint was effectiveness (ejection fraction (EF) increase, New York Heart Association (NYHA) class change, HF-related events). Exploratory endpoints included drug-drug interactions with anticancer and supportive care drugs, treatment of cancer therapy-related cardiac dysfunction (CTRCD), and changes in NT-proBNP. Results Eighty-three pts were enrolled (59 prospective - 24 retrospective). Median age was 71 (range 44-92) yrs, M/F 48/52%. The main cancer sites were breast, gastrointestinal tract, and hematological malignancies. Most cases (62%) received an active treatment (mainly chemotherapy) while on SGLT2i. Prevalent aetiology was drug-induced HF (37%) with reduced EF as the prevalent clinical presentation (39%). Prescribed agents were dapagliflozin in 60% and empagliflozin in 40% of cases on top of conventional guideline-directed medical therapy, with a median treatment duration of 3 (range 3-25) months. The incidence of urinary tract infection was 2.5%. No cases of genital infection, hypoglycemia, diabetic ketoacidosis, acute renal injury, thrombosis, and bone fractures were reported. Mean overall EF slightly increased (44.1% vs. 46.6%), and NYHA class improved (class improvement in 16%). Unplanned cardiology visits (1.2%), i.v. diuretics (1.2%), coronary angiography (5%), emergency access (2.5%), and new HF episodes (3.7%) rates were low. SGLT2i appeared effective in 31 cases of CTRCD. A relative reduction in mean NT-proBNP levels (2748 vs 1125pg/mL) was observed. No drug-drug interactions were reported. Conclusions SGLT2i appear to be safe and effective in active cancer patients with HF, with potential cardioprotective effect. No new safety warnings were recorded.

Heterogeneous effect of sodium-glucose cotransporter 2 inhibitors on cardiovascular events among people with type 2 diabetes: an application of machine learning to target trial emulation

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are widely used to reduce cardiovascular risk in patients with type 2 diabetes. However, certain patient subgroups, including younger individuals or those with lower body mass index (BMI), have been underrepresented in previous randomized clinical trials. Therefore, the consistency of the effectiveness of SGLT2i has not been thoroughly investigated. Purpose This research aims to investigate the individual benefit of SGLT2i on cardiovascular risk reduction across the diverse patient population with type 2 diabetes Methods We investigated the effectiveness of SGLT2i versus active comparators (dipeptidyl peptidase 4 inhibitors [DPP4i]) using a target trial emulation framework, prevalent new-user design, and a nationwide insurer-based database covering more than 30 million working-age citizens in Japan. Participants were identified using data from April 2015 to March 2022 and were followed until March 2023. The primary endpoint was the composite of all-cause death, myocardial infarction, stroke, or heart failure. We then applied the machine learning causal forest algorithm to the emulated trial cohort to predict the individualized benefit of SGLT2i in reducing cardiovascular outcomes. After describing the characteristics of patients with predicted benefits above the median (high-benefit group) and those with predicted benefits below the median (low-benefit group), we compared the long-term survival outcomes between the high-benefit group and the low-benefit group using adjusted Cox proportional hazard models. Results The study included 274,886 participants (SGLT2i, n=137,443; DPP4i, n=137,443) with a mean age of 55.7 years, 17.3% (n=47,517) female, and a mean BMI of 27.3kg/m2. Over a median follow-up of 36 months, 3.6% (n=9,896) experienced the primary outcome. SGLT2i were associated with a reduced incidence of the primary endpoint in the entire cohort (hazard ratio [HR] = 0.94 [95% confidence interval (95%CI): 0.90–0.97]). The causal forest model showed that the effects of SGLT2i were heterogeneous across individuals. Patients in the low-benefit group were characterized by older age, female gender, lower BMI, lower blood pressure, worse kidney function, and milder diabetes status than those in the high-benefit group. While we found the preventive effect of SGLT2i on long-term cardiovascular outcomes in the high-benefit group (HR [95%CI] = 0.86 [0.82–0.90]), the effect was not observed in the low-benefit group (HR [95%CI] = 1.05 [1.00–1.11]; p-for-interaction < 0.001). Conclusion By applying a machine-learning causal forest to a target trial emulation cohort in the general population, we found heterogeneity in the effect of SGLT2i on cardiovascular outcomes, and identified characteristics of patients who are less likely to benefit from SGLT2i. The findings suggest personalized treatment strategies for cardiovascular risk reduction in patients with type 2 diabetes.Graphical summary

What does routinely-collected electronic health record data tell us about the use of heart failure medication among older people in Wales? Making progress but could do better

Abstract Background European Society of Cardiology 2021 guidelines recommend 4 pillars of treatment to reduce mortality for those with heart failure (HF) and reduced ejection fraction (HFrEF): pillar 1) angiotensin converting enzyme inhibitor (ACE-I)/angiotensin receptor blocker (ARB)/angiotensin receptor-neprilysin inhibitor (ARNI), pillar 2) beta-blocker (BB), pillar 3) mineralocorticoid receptor antagonist (MRA), pillar 4) sodium-glucose co-transporter 2 inhibitor (SGLT2i). When there is heart failure with preserved ejection fraction (HFpEF), guidelines recommend diuretics to alleviate congestion and treatment of risk factors such as hypertension and diabetes. Prior to 2021, United Kingdom guidelines did not include SGLT2i. Purpose To examine how HF treatment is recorded in routinely-collected electronic health record (EHR) data for older people in Wales, and to explore how that has changed since 2015. Methods We conducted a retrospective, population-level, observational study using linked anonymised EHR data in Wales (2015-22). 737,230 individuals were aged 65y+ in the study period (21.5% of population in 2022). Of these, 65,010 had a code for heart failure in their primary or secondary care records. We excluded 13,990 individuals with fewer than 12 months data pre- or post-diagnosis. We looked forward, from HF diagnosis, for codes associated with specific medications. Results The final cohort comprised 51,020 individuals aged 65y and over with a diagnosis of heart failure between 2015-2022. Incidence and prevalence of heart failure increased across the study period (1.4-1.5% and 8.5-9.1% respectively). Preceding cardiovascular diagnoses included hypertension (69.5%), atrial fibrillation (36.7%), myocardial infarction (30.5%), coronary artery disease (25.7%), and valve disease (17.7%). Diabetes (41.7%), chronic kidney disease (30.9%) and cancer (26.4%) were the most common comorbidities. The subtype of HF (HFrEF or HFpEF) was only evident in 5,850. Treatments recorded most often were loop diuretics, ACE-I, and BB (Table 1). SGLT2i codes increased in 2020/2021(Figure 1). At 10-12 months post diagnosis, the proportion with simultaneous pillar combinations was; 27.4% 1 + 2, 12.5% 1, 2 + 3, and only 2% 1, 2, 3 + 4. Conclusions In Wales, there is a need to improve the coding of HF subtype in primary care records. We suggest interpreting data with the assumption that approximately half of the cohort are likely to have HFrEF. While the cohort proportion on ACE-I or beta-blockers may be appropriate, the proportion with more than 1 simultaneous pillar of treatment recorded appears low. The use of SGLT2i in codes is increasing. These results are important in evaluating health service delivery and in establishing baseline data from which to monitor improvements.

Combined class I and class III antiarrhythmic effects of sotagliflozin - insights from heterologous expressions systems and atrial cardiomyocytes

Abstract Background The demand for more effective treatment options for atrial fibrillation (AF), the most common sustained arrhythmia, is driven by its direct impact on morbidity and mortality. Current therapies, such as antiarrhythmic drugs and catheter ablation, are limited by suboptimal efficacy and adverse effects or periinterventional complications. Therefore, safe and effective treatment of AF remains a major unmet clinical need. Sodium-glucose cotransporter (SGLT) inhibitors have shown promise in reducing the incidence of AF in large cardiovascular endpoint trials. However, the exact mechanisms of action remain unclear. While only two SGLT2 inhibitors are approved and clinically used in Europe, sotagliflozin, which inhibits both SGLT1 and SGLT2, might also have potential for the treatment of AF. Purpose This study aims to elucidate the effects of sotagliflozin on cardiac action potential formation. This understanding could optimise its clinical use, identify new targets for the treatment of atrial fibrillation and ultimately improve the quality of life of patients suffering from AF. Methods The effects of sotagliflozin on cardiac ionic currents were assessed using two-electrode voltage clamp measurements of several sodium and potassium channels heterologously expressed in Xenopus laevis oocytes. Subsequently, ascending concentrations of sotagliflozin were administered to isolated human atrial cardiomyocytes during patch-clamp measurements to investigate its effect on atrial action potential morphology. Results At a concentration of 100 µM, sotagliflozin showed significant inhibitory effects on three out of ten ion channels tested: NaV1.5 sodium channel current was reduced by 22,3 % %, hERG and KV4.3 potassium currents were reduced by 30,4 % and 22,5 % respectively. Patch-clamp experiments, performed on isolated human atrial cardiomyocytes showed a dose-dependent reduction in upstroke velocity and action potential amplitude by 20,8 % and 13,8 % at a concentration of 20 µM, reflecting class-I-antiarrhythmic effects. Furthermore, a prolongation of AP duration measured at 50 % (APD50) and 90 % (APD90) of repolarization by 57,7 % and 27,9 % at a sotagliflozin concentration of 20 µM was noted, implying additional class-III-antiarrhythmic action. Conclusions Sotagliflozin exerts direct inhibitory effects on heterologously expressed NaV1.5, hERG and KV4.3 channels, resulting in a reduction in upstroke velocity and action potential amplitude, as well as a prolongation of APD50 and APD90 levels in isolated human atrial cardiomyocytes. These results extend the pharmacological profile of sotagliflozin and suggest a potential role for the clinical use of combined SGLT1/SGLT2 inhibitors in the treatment of AF.

Combined ARNI and SGLT2i impacts on peak tricuspid regurgitant velocity and echocardiographic probability of pulmonary hypertension

Abstract Background In heart failure with reduced ejection fraction (HFrEF), the development of pulmonary hypertension (PH) is associated with poor prognosis. Recent medical advancements have substantially improved both survival rates and HF hospitalization. However, the impact of combining angiotensin receptor neprilysin inhibitor (ARNI) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) on peak tricuspid regurgitant velocity (TRV) and PH echocardiographic probability remains unexplored. Purpose We aimed to evaluate the effect of ARNI alone versus ARNI combined with SGLT2i on peak TRV and PH probability in a real-life population of outpatients with HFrEF. Methods This was an observational monocentric study including patients treated with either ARNI alone or with SGLT2i on top of ARNI. Echocardiographic examinations were performed by fully accredited operators and all parameters were analysed offline by expert operators blinded to clinical data. We performed echocardiographic evaluation in all patients before initiating treatment and at 12 months follow-up. We excluded patients who discontinued ARNI within 6 months of introduction and those who did not complete at least 6 months of follow-up with both drugs. Results 80 HFrEF patients were included, 41 receiving ARNI+SGLT2i and 39 receiving ARNI alone. Baseline mean peak TRV was similar between the two groups (280±44 cm/s and 259±48 cm/s respectively, p=0.09). At follow-up, mean peak TRV was 232±32 cm/s in ARNI+SGLT2i group and 258±45 cm/s in ARNI alone group (p=0.02). The decrease in peak TRV was significant in ARNI+SGLT2i group, p=0.0004 (Table). At baseline the echocardiographic probability of PH was comparable between both groups, p=0.53 (Figure). Nevertheless, during follow-up, the proportion of patients with high probability of PH decreased in the ARNI+SGLT2i group (from 22% to 2%), while in the ARNI alone group it did not change (Figure). Conclusions In HFrEF the combination of ARNI+SGLT2i demonstrates high effectiveness in TRV reduction, downgrading PH probability class. In our population, this evidence is primarily driven by the decrease TRV. These results may suggest the positive effect of SGLT2i on pulmonary vascular remodelling and right heart hemodynamic worth of full investigation in further studies aimed at targeting left-sided PH and its prevention strategies.

SGLT2-'eyes' on the reno-protection prize: reduction of post-PCI contrast-associated AKI in diabetic patients using SGLT2 inhibitors

Abstract Background Chronic therapy with sodium-glucose cotransporter 2 inhibitors (SGLT2i) is associated with long term reno-protective benefits. There are limited data on the benefits of these agents against the risk of contrast-associated acute kidney injury (CA-AKI). Purpose The goal of our study was to assess the comparative efficacy of SGLT2i for the prevention of CA-AKI in diabetic patients undergoing PCI. Methods The study population included all diabetic patients enrolled in the Blue Cross Blue Shield of Michigan Cardiovascular Consortium Percutaneous Coronary Intervention (BMC2PCI) registry, a clinical registry of all PCI cases at non-federal hospitals in the state of Michigan, USA. Included patients underwent PCI between January 2022 and September 2023. Patients on dialysis were excluded. Predicted AKI risk was calculated using a previously validated and published machine learning BMC2 risk model. The primary outcome of CA-AKI was defined as an elevation in serum creatinine of ≥0.5 mg/dL following PCI. Risk-adjusted AKI rates were estimated by the product of event observed/expected ratio and overall collaborative AKI rate. Propensity matching on 23 covariates was used to adjust for the non-random use of SGLT2i. Results A total of 19,078 diabetic patients were included, of whom 3,087 (16.2%) were prescribed SGLT2i prior to PCI. Patients treated with SGLT2i were younger (66.1 vs 68.3 years), more likely to be men (73.3% vs 65.3%), have heart failure (50.4% vs 42.4%), have prior PCI (58.4% vs 48.8%), and have co-prescription of insulin (43.8% vs 37.3%) (p<0.001 for all). After propensity matching, no significant baseline difference between cohorts remained, with an absolute standardized difference less than 10% on all covariates. The pre-procedural use of SGLT2i was associated with a lower incidence of CA-AKI in unadjusted analysis (2.7% vs 3.8%, p=0.003) and after adjusting for the baseline predicted risk of CA-AKI (2.2% vs 2.8%, adjusted OR 0.69, 95% CI 0.54-0.89, p=0.0045). In a propensity-matched analysis, the use of SGLT2i was strongly associated with a reduced adjusted risk for CA-AKI (2.2 % vs 2.8%, adjusted OR 0.72, 95% CI 0.62-0.84, p=0.026). Conclusions Among patients with diabetes presenting for PCI, pre-procedural use of SGLT2i was associated with a significant reduction in the risk of CA-AKI. These results should compel further investigation into the beneficial effects of SGLT2 inhibitors in reducing the risk of CA-AKI.

The effect of empagliflozin on circulating endothelial progenitor cells in patients with diabetes and stable coronary artery disease.

Diabetes mellitus (DM) is associated with premature atherosclerotic disease, coronary artery disease (CAD) and chronic heart failure (HF), leading to increased morbidity and mortality. Sodium-Glucose Co-transporter 2 Inhibitors (SGLT2i) exhibit cardioprotective benefits beyond glucose lowering, reducing the risk of major cardiovascular events (MACE) and HF hospitalizations in patients with DM and CAD. Endothelial progenitor cells (EPCs) are bone marrow-derived cells involved in vascular repair, mobilized in response to vascular injury. The number and function of circulating EPCs (cEPCs) are negatively affected by cardiovascular risk factors, including DM. This study aimed to examine the response of cEPCs to SGLT2i treatment in DM patients with stable CAD. A prospective single-center study included patients with DM and stable CAD who were started on an SGLT2i (empagliflozin). Peripheral blood samples were collected at baseline, 1 month, and 3 months to evaluate cEPC levels and function by flow cytometry, immunohistochemistry and MTT assays. Eighteen patients were included in the study (median age 73, (IQR 69, 77) years, 67% male). After 1 month of treatment with empagliflozin, there was no significant change in cEPCs level or function. However, following 3 months of treatment, a significant increase was observed both in cell levels (CD34(+)/VEGFR-2(+): from 0.49% (IQR 0.32, 0.64) to 1.58% (IQR 0.93, 1.82), p = 0.0006; CD133(+)/VEGFR-2(+): from 0.38% (IQR 0.27, 0.6) to 0.82% (IQR 0.7, 1.95), p = 0.0001) and in cell function (from 0.25 CFUs (IQR 0, 0.5) at baseline, to 2 CFUs (IQR 1, 2) at 3 months, p = 0.0012). Empagliflozin treatment in patients with DM and stable CAD increases cEPC levels and function, implying a cardioprotective mechanism. These findings highlight the potential of SGLT2i in treating cardiovascular diseases, warranting further research to explore these effects and their long-term implications.

SGLT2 inhibitor empagliflozin prevents anthracycline-induced cardiotoxicity in a large-animal model

Abstract Background While the development of cancer therapies has significantly improved the survival of cancer patients, more than 35% of cancer survivors treated with anthracyclines will develop cardiotoxicity. There is currently a lack of preventative therapies against anthracycline-induced cardiotoxicity (AIC). AIC is characterised by a disruption in myocardial metabolism. Sodium-glucose co-transporter (SLGT2) inhibitors represent a potential therapy as they have been shown to modulate myocardial substrate utilisation in other heart-failure contexts. Purpose We developed a highly translational large-animal model to test the ability of SGLT2 inhibitor empagliflozin to prevent AIC at different doses. Methods Female Large-White pigs were randomised (2:1:1) to no treatment (AIC-control group) or empagliflozin at a daily oral dose of 10 mg or 20 mg, beginning at the start of the doxorubicin regimen and continuing to 21 weeks. All pigs received 6 doses of doxorubicin intravenous infusion (25 mg/m2/every 3 weeks) with 2 additional off-dose visits. Pigs were assessed by cardiac magnetic resonance (CMR) and MR spectroscopy (MRS) at baseline and every 3 weeks for 21 weeks. At the end of 21-week follow-up, the LV was collected and processed for analysis by transmission electron microscopy (TEM) and mitochondrial respirometry. Results The primary outcome, final LVEF, was significantly higher in pigs receiving 20 mg empagliflozin than in the AIC-control group (57.5% (IQR=55.5, 60.3) vs 47.0% (40.8, 47.8); p=0.027). Final LVEF in pigs receiving 10 mg empagliflozin was 51% (46.5, 55.5) (p=0.020 vs 20 mg empagliflozin). The 20 mg empagliflozin dose prevented the doxorubicin-induced change in cardiac metabolic substrate utilisation and was associated with preservation of myocardial energetics (ATP/PCr ratio on MRS). TEM revealed disrupted mitochondrial structure and cristae density in AIC-control pigs, while mitochondria respirometry detected deteriorated respiratory function. Both mitochondrial structure and function were preserved in empagliflozin-treated pigs, with the 20 mg dose having the strongest cardioprotective effect. Conclusion The results from our translational large-animal model provide strong evidence that SGLT2 inhibition with empagliflozin prevents AIC by preserving LV systolic function and energetics as well as mitochondrial structural integrity and function. Our results establish the basis for clinical trial testing SGLT2i therapy in patients at high risk of AIC.

Effects of sodium-glucose cotransporter 2 inhibitors on pulmonary hemodynamics in chronic heart failure patients with a pulmonary artery pressure sensor

Abstract Background Approximately 50% of patients with chronic heart failure (HF), either with preserved or reduced left ventricular ejection fraction (LVEF), have secondary pulmonary hypertension, which results in poorer prognosis. In previous studies, sodium-glucose cotransporter 2 inhibitors (SGLT2i) have shown a reduction in cardiovascular death, HF hospitalization and pulmonary artery pressure (PAP) in patients with HF, regardless of LVEF, but exact mechanisms remain unclear. Purpose The main objective of this study is to analyse effects of SGLT2i on PAP in patients with chronic HF followed by a PAP sensor (CardioMEMS HF system). The secondary objective is to analyse effects in subgroups of LVEF. Methods We included chronic HF patients (regardless of LVEF) with previously implanted a PAP sensor, from July 2019 to February 2023. SGLT2i had been added in fourth position in patients with reduced LVEF, since they were previously on optimal HF treatment as chronic patients. Changes in PAP, renal function and N-terminal pro B-type natriuretic peptide (NTproBNP) were compared between two periods of time: "30 days before" and "30 days after" SGLT2i initiation. Patients were then classified in two groups: group 1 (LVEF ≤40%) and group 2 (LVEF >40%) and repeated same analyses. Results Overall, 61 patients were screened, and 17 finally were included, mean age 71.7 ± 9.6 years, 64.7% were men, mean LVEF was 49.4 ± 17.5%, 23.5% had ischaemic aetiology and 64.7% were in NYHA class III (Table 1). There were more men in group 1 than in group 2 (p=0.043), without other differences in basal characteristics between groups (Table 1). Dapagliflozin (10mg daily) was initiated in 14 patients (82.4%), 5 from group 1 and 9 from group 2 (p=1.000), and empagliflozin (10mg daily) in 3 patients (17.6%), 1 from group 1 and 2 from group 2 (p=1.000). Before SGLT2i, mean diastolic PAP (dPAP) was 17.3 ± 5.6 mmHg and median NTproBNP was 2841.5 (289-10515) pg/mL. SGLT2i significantly reduced dPAP; average dPAP ("30 days after" period) was 1.5 mmHg lower (95% CI, 0.26-2.74; p=0.021) compared to "30 days before" period (Figure 1). SGLT2i also reduced systolic PAP (-2.2 mmHg), mean PAP (-1.7 mmHg), NTproBNP (-183 pg/mL) and creatinine (-0.2 mg/dL), but not statistically significant. SGLT2i reduced PAP, NTproBNP and creatinine too in group 1 (6 patients), but did not achieve statistical significance. Reductions were as well observed in group 2 (11 patients), and SGLT2i significantly reduced dPAP (-2.04 mmHg) (95% CI, 0.31-3.77; p=0.025). Conclusions In patients with chronic HF and a PAP sensor, SGLT2i, added to previous HF treatment, significantly reduced dPAP. PAP reductions were observed regardless LVEF, but results were more robust in patients with LVEF >40%.Figure 1

Assessing the practicality of a novel heart failure therapeutic score (QUAD Score) for drug optimisation in heart failure with a reduced ejection fraction

Abstract Introduction The 4 pillars of drug treatment for heart failure with a reduced ejection fraction (HFrEF) [Angiotensin-converting enzyme inhibitors (ACEi)/Angiotensin receptor–neprilysin inhibitors (ARNi), β-blockers (BB), Mineralocorticoid receptor antagonists (MRA), and Sodium-glucose cotransporter 2 inhibitors (SGLT2i)], are recommended by international HF guidelines to improve patient outcomes. Treatment inertia remains a challenge with non-prescription or sub-optimal dosing of these therapies. We developed a pragmatic HFrEF treatment score (QUAD score) (Figure 1) to prompt initiation and/or titration of sub-optimally dosed foundational therapies. Patients are categorized as poor (<8), good (8-14), and excellent (15-24) based on the dose and number of foundational drugs prescribed. This study aims to assess the practical utility of the QUAD score and its influence on treatment optimization. Methods Unwarned prescribing HCPs were approached consecutively in person, within clinical settings. Participants were told the questions were part of a research project and they provided verbal consent. Responses were anonymous and no patients were involved; therefore, verbal consent was considered proportionate and reasonable. HCPs were given an information sheet describing the QUAD score (Figure 1). They were then presented with 3 hypothetical clinical scenarios of haemodynamically stable and uncomplicated HFrEF patients with uncalculated poor, good and excellent QUAD scores. They were asked to calculate the QUAD score and if they proposed any changes to treatment. Time was recorded using a stopwatch and proposed changes were recorded. They were then invited to answer a series of follow-on questions. Results Between September 2023 and February 2024, there were 70 respondents. 71% (50) were doctors and 29% (20) allied HCPs. 83% (58) placed patients in the correct treatment grade in at least one scenario. 62.9% (44) did so for all three scenarios (Figure 2) with numerically more HCPs compared to doctors (80% vs 56% p=0.06).The median (IQR) time in seconds required to calculate the QUAD score for clinical scenarios 1,2 and 3 was 158 (100-234), 86 (54-122) and 83 (53-119) respectively. In response to the calculated QUAD score, 94.3% (66), recommended drug treatment optimisations. On a 5-point Likert scale (1 -poor, 5- excellent), 77.1% of participants rated the QUAD score ≥3 for ease of use, and 88.6% rated ≥3 as an incentive for treatment optimization. Conclusion We demonstrated the rapid clinical usability of the QUAD Score in a cohort of unselected prescribing HCPs, with a decremental calculation time with each presented clinical scenario. HCPs were also motivated to achieve further HF drug therapy optimization based on the calculated score. We conclude that the QUAD Score as a HFrEF drug therapy score may have a role in addressing treatment inertia however, it needs validation against clinically relevant outcomes in a larger cohort of HFrEF patients.

Unravel novel therapeutic targets in heart failure and associated pulmonary hypertension

Abstract Background Heart Failure (HF) is a complex clinical syndrome with poor prognosis. Pulmonary hypertension (PH) often complicates HF but can hardly be addressed therapeutically. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) improve cardiovascular outcomes in patients with HF. Whether SGLT2i positively impact on HF-associated PH is poorly understood. Omics offer great promise in the discovery of novel biomarkers and therapeutic targets for HF and PH. Aims We investigated novel markers associated with HF and PH, as well as how these biomarkers vary in response to HF-modyfing therapies, including SGLT2i. We also explored the impact of SGLT2i, compared with conventional anti-HF therapy, on HF-associated PH and right ventricular function. Methods Seventy-four patients with HF and reduced ejection fraction (HFrEF) with/without diabetes were divided into a gliflozin (G)-group receiving 10 mg/day empagliflozin or dapagliflozin, and a control (C)-group receiving conventional anti-HF therapy. Resting echocardiography, analyses on senescence markers [leucocyte telomere length (LTL), mitochondrial DNA copy number (mtDNAcn)], as well as measurement of two microRNAs (miRNA-21 and miRNA-92, recently implicated in response to treatment in HFpEF patients), were performed. Shotgun proteomic analyses were conducted on peripheral blood mononuclear cells. Results Compared to group C, group G had a significantly higher ejection fraction (EF, 42±13 vs 33±8, p=0.001), reduced left ventricular filling pressures (11±3 vs 15±5, p=0.001), reduced pulmonary artery systolic pressure (PAPs, 31±11 vs 46±15, p=0.001), better right ventricular-pulmonary artery coupling index (0.64±0.31 vs 0.44±0.22, p=0.002), increased LTL (Figure 1 A), higher mtDNAcn (Figure 1 B), reduced miRNA-21 levels (Figure 1 C) and no significant changes of miRNA-92 (Figure 1 D). Functional proteomic analysis showed that, compared with the C-group, the protein cargo from the G-group was able to trigger several biological pathways, showing a significant activation of T lymphocytes immune response (p-value=9.67x10-06, z-score=2.21) chemotaxis of monocytes (p-value=9.39x10-07, z-score=2.0), leukocytes (p-value=9.67x10-10, z-score=2.0)and phagocytes (p-value)=3.10x10-10, z-score=2.03) (Figure 2). Compared with the C-group, the G-group showed a downregulation of activin signaling pathway (z-score=-2.12), which is a novel therapeutic target in pulmonary arterial hypertension (PAH). Conclusions In HF patients, SGLT2i therapy is associated with improved left ventricular function and improved pulmonary hemodynamics. Activin is overactive in HF patients and its serum levels may be reduced by SGLT2i. SGLT2i may preserve LTL and mtDNA-cn as well as modulate the expression of specific miRNA implied in the regulation of endothelial function. SGLT2i may represent an additional therapeutic tool in patients with HF-associated PH, an area with no approved treatment options beyond traditional HF therapy.Figure 1:genomic analysesFigure 2:proteomic analyses