SGLT2 Research Articles

The impact of sodium glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists on insulin utilisation and costs in Australia: a national retrospective observational cross-sectional study

Global insulin requirements for type 2 diabetes were predicted to increase by more than 20% from 2018 to 2030. However, this did not anticipate the rapid increase in use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors that has occurred over recent years. The current study aims to examine changes in insulin utilisation and costs in Australia from 2003 to2023. We conducted a large-scale observational study of national insulin utilisation and expenditure in Australia from 2003 to 2023 using the Australian Pharmaceutical Benefits Scheme. The proportion of insulin-treated people with type 2 diabetes between 2013 and 2023 was estimated using National Diabetes Services Scheme data. Joinpoint models and interrupted time series analysis were used to examine utilisation trends. Insulin utilisation (units of insulin per person with diabetes) increased by an average of 2.71% per annum (95% CI 1.97, 3.73) from 2003 to 2015, then fell by 2.70% per annum (95% CI-4.55,-1.39) from 2015 to 2023. The proportion of insulin-treated people with type 2 diabetes increased by 1.00% per annum (95% CI 0.81, 1.25) from 2013 to 2020, then fell by 0.66% per annum (95% CI-1.62,-0.04) from 2020 to 2023. A 43% reduction in inflation-adjusted insulin expenditure was observed between 2015 and 2023 due to a combination of reduced utilisation and reduction in the price of insulin glargine. Projected global insulin requirements and costs may be less than previously anticipated if reduced use of insulin in Australia is similarly observed in other countries. No funding was received for this study.

Outcomes of Pediatric Liver Transplantation in Glycogen Storage Disease Type 1b-A Single-Center Experience.

Liver transplantation (LT) normalizes fasting tolerance in glycogen storage disease type (GSD) 1b. However, reported outcomes post-LT with respect to correction of neutropenia, infection risk and growth are varied. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have been recently shown to improve neutropenia in GSD1b patients. In this single-center retrospective study, we reviewed all children who underwent LT for GSD1b. Neutropenia, dose of granulocyte colony-stimulating factor (G-CSF), unplanned hospital attendance, anthropometrics, graft rejection, survival, and the effects of dapagliflozin were analyzed. Data from protocol biopsies obtained at 1, 5, and 10 years post-LT and immunosuppression levels were collected. Eight children (6 female), all on G-CSF pre-transplant, underwent cadaveric LT for GSD1b at median age 3.6 years (IQR 3.3-5.1) with mean follow-up time of 10.3 years (95% CI 7.5-13.1). Neutrophil count and G-CSF requirement did not improve post-LT. Although a reduction in unplanned hospital attendance due to infection (0.98 [95% CI 0.76-1.26] vs. 0.49 [95% CI 0.41 to 0.57] per person-year, p < 0.01) was observed, gastrointestinal complaints and graft dysfunction accounted for a similar hospitalization burden pre- versus post-LT. Body mass index (BMI) reduced post-LT (Z-score 1.47 [95%CI 0.39-2.23] vs. 0.56 [95% CI -0.74 to 1.45], p = 0.02), with no significant change in height. Although all children and grafts have survived, 75% of recipients developed rejection, despite adequate immunosuppression levels, with two children having been found to have developed significant fibrosis on their 5-year protocol biopsy. Although dapagliflozin allowed cessation of G-CSF, no improvement in neutrophil count was observed. Despite this, a reduction in gastrointestinal and infection-related morbidity was noted following dapagliflozin. Although LT normalizes fasting tolerance in GSD1b and reduces hospital attendance due to infection, morbidity from infection and gastrointestinal manifestations persist. Children in our cohort experienced high rates of rejection necessitating titration of immunosuppression to balance risk of infection against organ rejection. Future studies should investigate whether early introduction of SGLT2 inhibitors post-LT impact morbidity in this group.

Utilization and cost of non-insulin glucose-lowering drugs in Australia from 2013 to 2023.

To investigate the utilization and costs of non-insulin glucose-lowering drugs (GLDs) in Australia from 2013 to 2023. We conducted a retrospective analysis of the Australian Pharmaceutical Benefits Scheme (PBS) administrative dataset of 118 727 494 GLD prescriptions. The main outcome measures were the annual number of GLD prescriptions dispensed, accounting for type 2 diabetes mellitus (T2DM) prevalence and healthcare system costs, adjusted for inflation. Utilization of GLDs doubled from 6.4 million prescriptions in 2013 to 15.6 million in 2023. The average annual percent increase in utilization was 8.1%, compared to the average annual increase in prevalence of T2DM of 1.8%. The biggest change was in sodium-glucose cotransporter-2 (SGLT2) inhibitors, for which there was an average annual increase in utilization of 59.4% (95% confidence interval [CI] 51.7%, 68.2%; p < 0.05) from 2014 (first full year of PBS listing), followed by glucagon-like peptide-1 receptor agonists (GLP-1RAs), which showed an increase of 31.4% (95% CI 28.5%, 33.8%; p < 0.05) annually (2013 to 2023). Dipeptidyl peptidase-4 inhibitor utilization tripled, with an average annual increase of 10.9% (95% CI 8.1%, 13.8%; p < 0.05), but this plateaued from 2020. Metformin utilization increased by 4.7% (95% CI 2.0%, 6.9%; p < 0.05) annually. In contrast, sulphonylurea, glitazone and acarbose utilization declined. Total GLD costs increased threefold over the same period. Despite only accounting for 11.7% of utilization, GLP-1RAs contributed to 35% of the costs. Utilization of GLDs doubled, and associated costs tripled over the past 11 years, with no sign of either utilization or costs plateauing, predominantly due to increased GLP-1RA and SGLT2 inhibitor prescribing.

Guidelines, heart failure and the elderly

Heart failure (HF) guidelines have recently introduced several innovations in pharmacological therapeutic options. Specifically, for HF with reduced ejection fraction, an intensive therapeutic strategy of early initiation and rapid up-titration of guideline-directed medical therapy is now recommended in all patients to reduce the risk of HF rehospitalization or death. In clinical practice, however, this approach is not always feasible in the elderly population due to the coexistence of multiple geriatric conditions such as frailty, comorbidities in addition to the risk of adverse drug effects, general prescribing inertia and the unmet need for close follow-up during drug up-titration. As for HF with preserved ejection fraction, sodium-glucose cotransporter 2 inhibitors have been shown to significantly reduce the composite outcome of HF hospitalization and cardiovascular mortality. However, these drugs have not yet been proven effective in some cardiomyopathies, as these were not included in clinical trials. This review aims to provide a critical analysis of current HF guidelines, illustrating their limits in real-world applicability through a cardio-geriatric lens reinterpretation of recent evidence.

Medication optimization clinic decreases hospitalizations and mortality for patients with heart failure with reduced ejection fraction

Study objectiveTo evaluate the impact of a medication optimization clinic (MOC) on GDMT and outcomes for patients with HFrEF versus usual care. DesignRetrospective evaluation of a multi-site MOC was conducted. SettingLarge health system with academic and community hospitals. ParticipantsPatients with HFrEF referred to MOC by their cardiologist versus usual care. InterventionsGDMT use managed by an advanced practice provider or clinical pharmacist through weekly telemedicine visits. Main outcome measuresThe primary outcome was HF hospitalization. Cardiovascular hospitalization and all-cause mortality were also assessed. Kaplan−Meier Curve, Cumulative Incidence Function, and competing risk analysis with regression models were conducted. Results1419 patients in MOC group were compared to 5116 control patients. GDMT use was significantly higher in MOC: quadruple therapy (49 % vs. 19 %; p < 0.0001), angiotensin-receptor neprilysin inhibitor (62 % vs. 45 %; p < 0.0001), beta blocker (92 % vs. 88 %; p < 0.0001), mineralocorticoid receptor antagonist (69 % vs. 45 %; p < 0.0001), and sodium glucose cotransporter-2 inhibitor (68 % vs. 35 %; p < 0.0001). Competing risk analyses showed that HF and CV hospitalizations were significantly lower at all times points (3, 6, and 12 months) for MOC vs. control (p < 0.001). All-cause mortality was significantly lower at 6 months (p = 0.006) and 12 months (p < 0.001), but did not differ at 3 months (p = 0.35), for MOC vs. control. ConclusionsMOC was associated with improved GDMT and lower risks of hospitalizations due to HF and any cardiovascular cause, and all-cause mortality in patients with HFrEF.

Sodium-Glucose Cotransporter-2 Inhibition Normalizes Metabolic Derangements in the Ischemic Myocardium

IntroductionSodium-glucose cotransporter-2 inhibitors (SGLT2i) have shown efficacy in the context of heart failure but have not been well-studied in ischemic heart disease. We employed a large animal model of chronic coronary artery disease and metabolic syndrome (MS) to investigate the hemodynamic and metabolic consequences of SGLT2i administration. MethodsThirty-eight Yorkshire swine were divided into two groups, with half (n = 21) receiving a high fat diet to induce MS, and the other half fed a standard diet (n = 17). All animals underwent thoracotomy for ameroid constrictor placement over the left circumflex coronary artery. Treatment with SGLT2i was then initiated, generating four groups: regular diet placebo (CON, n = 9), regular diet canagliflozin (n = 8), high-fat control (n = 11), and high-fat canagliflozin (n = 10). After 5 wks, all animals underwent terminal myocardial harvest with pressure-volume loop acquisition, perfusion studies, and tissue resection for molecular analysis. ResultsSGLT2i improved multiple measures of myocardial performance, including a nearly 1.5-fold increase in both cardiac output and ejection fraction; these changes were associated with augmented capillary density and a twofold increase perfusion to the ischemic myocardium. These augmentations were blunted; however, in the presence of MS, and associated with modulated myocardial expression of multiple major metabolic enzymes. ConclusionsSGLT2i significantly improved cardiac function in our large animal model of coronary artery disease, with metabolic modulation of the myocardial tissue serving as a candidate account of these changes. The blunting seen with MS underscores the dependence of clinical translatability on faithful representation of the biochemical environment of human disease.

NOVEL AGENTS IN THE MANAGEMENT OF DIABETES AND RISK OF WORSENING DIABETIC RETINOPATHY.

Novel therapies for diabetes have potent effects on glycemic control, obesity, and cardiovascular risk reduction, but some, including the popular drug semaglutide, have also been implicated in worsening of diabetic retinopathy (DR). Given the ubiquity of these new agents, understanding the risks to vision is important. Here, we review the data for several newly available agents in terms of systemic efficacy and retinal safety. Literature review. Novel antihyperglycemic treatments include incretin mimetics and enhancers, sodium-glucose cotransporter inhibitors, long-acting insulins, and insulin delivery systems. All improve glycemic control, and some have been shown to reduce major cardiovascular outcomes. In a pivotal trial, semaglutide was associated with approximately 75% increased risk of DR worsening. The novel long-acting insulin icodec, formulated for once weekly dosing, showed increased risk of DR worsening over a once daily insulin. No other recent antihyperglycemic agent was associated with DR worsening, although following the semaglutide trials, nearly all studies excluded patients with preexisting DR. Cases of DR worsening were rare in all instances. Dedicated safety studies for semaglutide in DR are currently underway. For most patients being considered for treatment with a novel antihyperglycemic agent, benefits on systemic metabolic and cardiovascular health are very likely to outweigh potential retinal harms. Although the true risks of the new agents on DR are unclear because their safety data come from secondary end points, the most vulnerable patients are those with preexisting high-risk DR, poor baseline glycemic control, and using insulin.

Sodium-glucose cotransporter-2 inhibitors in acute myocardial infarction: a systematic review and meta-analysis of randomized controlled trials.

We aimed to assess the efficacy and safety of sodium-glucose cotransporter-2 inhibitors (SGLT2i) versus placebo, initiated within the hospitalization period, in addition to habitual treatment, for treating adult patients with confirmed acute myocardial infarction (AMI). We also conducted subgroup analysis by diabetes mellitus (DM) status and type of AMI. We systematically searched PubMed, Embase, and Cochrane Library for randomized controlled trials (RCTs). The primary outcome was hospitalization for heart failure (HF). The secondary outcomes were all-cause death, cardiovascular death, and serious adverse events (AEs). We pooled risk ratios (RR) with a 95% confidence interval (CI) for binary outcomes. The between-study variance was assessed using tau2 statistics. We included five RCTs, encompassing 11,211 patients. SGLT2i significantly reduced the risk of hospitalization for HF compared to placebo (RR 0.73; 95% CI [0.61, 0.88]). However, the risk of all-cause death (RR 1.05; 95% CI [0.78, 1.41]) and cardiovascular death (RR 1.04; 95% CI [0.84, 1.29]) was similar between the groups, as well as the risk of serious AEs (RR 1.01; 95% CI [0.90, 1.14]). In the subgroup analysis by DM status and type of AMI, there were no significant subgroup differences for the outcomes of hospitalization for HF and all-cause death. In patients with AMI, treatment with SGLT2i is safe and significantly reduces the risk of hospitalization for HF, but it has no impact on all-cause death and cardiovascular death compared to placebo.

Impact of SGLT2 inhibitors on liver-related outcomes in patients with heart failure - a population-based study in HK

Abstract Background Sodium-glucose cotransporter-2 (SGLT2) inhibitors are now recommended for heart failure with preserved ejection fraction (HFpEf). While their side effects on respiratory and renal outcomes in patients with type 2 diabetes have been studied, the impact on liver-related diseases within HF patients is not well-established. Purpose This study aims to evaluate the association between SGLT2 inhibitor use and the risks of adverse liver events among HF patients. Methods We conducted a retrospective cohort study using the Hong Kong Clinical Data Analysis and Reporting System (CDARS) to identify 80,248 HF patients (mean age 73.37 ± 12.88 years; 49.2% male) between 2013 and 2022. Propensity score matching was applied to achieve a 1:3 ratio of SGLT2 users to non-users, ensuring balanced baseline characteristics. Competing risk regression within Cox proportional hazards frameworks quantified the risks for cirrhosis, hepatocellular carcinoma, liver-related death, and significant elevations in liver enzymes (ALT or AST &amp;gt;3x normal and bilirubin &amp;gt;2x normal). Results During a median follow-up of 6.02 years (interquartile range: 3.48–9.25 years), there were 12,103 liver-related deaths. SGLT2 was associated with a 52% reduced risk of cirrhosis (adjusted subdistribution hazard ratio [SHR]: 0.48; 95% confidence interval [CI]: 0.36-0.65), a 61% lower risk of hepatocellular carcinoma (SHR: 0.39; 95% CI: 0.26-0.42), a 13% decreased risk of liver-related death (SHR: 0.87; 95% CI: 0.77-0.98), and a 19% risk reduction in elevated liver enzymes (SHR: 0.81; 95% CI: 0.68-0.96). 5-year cumulative incidences were 1.7%, 0.62%, 13%, and 5.4%, respectively, for SGLT2 users compared to 3.7%, 1.9%, 16%, and 7.0% for SGLT2 nonusers. Conclusion SGLT2 use is associated with a decreased risk of adverse liver outcomes in HF patients. This suggests a potential protective role for SGLT2 in liver health within this population.

The role of sodium-glucose cotransporter 2 (SGLT2) inhibitors in epicardial adipose tissue modulation: a meta-analysis

Abstract Introduction Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as a groundbreaking class of antidiabetic medications, renowned for their glucose-lowering effects and cardiovascular benefits. Recent studies have suggested that SGLT2 inhibitors may extend their influence beyond glycemic control to impact adipose tissue physiology, particularly within the epicardial adipose depot. Epicardial adipose tissue (EAT), an actively secretory organ surrounding the heart, has been implicated in the modulation of cardiovascular risk. Purpose This meta-analysis aims to systematically review and synthesize existing literature on the effects of SGLT2 inhibitors on epicardial adipose tissue. Methods We performed a literature search for studies assessing epicardial adipose tissue before and after treatment with a SGLT2 inhibitor compared to a control group. We excluded reviews, editorials, case reports/case series, and studies that did not use SGLT2 inhibitors or did not have a control group for comparison. The main outcome of interest was the change in EAT volume/thickness at follow-up. Effect sizes are presented as standardized mean difference (SMD) with their corresponding 95% confidence intervals (CIs) and were pooled based on a random-effects model. The leave-one-out sensitivity analysis was used for further validation of the findings. Publication bias was assessed by funnel plot inspection and egger’s regression test. Results The literature search yielded 49 results. After application of the exclusion criteria, a total of 6 studies were selected for data extraction and inclusion in the meta-analysis. Accordingly, we detected that treatment with an SGLT2 inhibitor was associated with decreased EAT volume/thickness (SMD -1.79, 95% CI -2.91 to -0.66, p&amp;lt;0.01). There was substantial between-study heterogeneity (I2: 94%, p&amp;lt;0.01). Results remained robust even after exclusion of any single study. Funnel plot inspection and egger’s regression test did not indicate the presence of publication bias. Conclusion This meta-analysis suggests that SGLT2 inhibitors use is associated with a reduction in EAT volume/thickness, posing as a potential mechanism of their beneficial effects in heart failure outcomes.Figure

Myocardial SGLT2 expression and cardiac remodeling in patients with severe aortic stenosis: the BIO-AS Study

Abstract Background Cardiac remodeling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Blood and tissue biomarkers have a differential pattern and expression level in patients with AS, which may retain a pathophysiological role in cardiac remodeling and metabolism. However, the data available are limited and contradictory. Aim Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments. Methods Gene expression and protein levels of main biomarkers of cardiac fibrosis (Galectin-3, sST2, Serpin-4, PINP, PICP, Collagen, TGF-b), inflammation (GDF-15, IL-6, NF-kB), oxidative stress (SOD1, SOD2), and cardiac metabolism (NHE, PPAR-a, PPAR-g, GLUT1, and GLUT4) were evaluated in blood samples and heart biopsies of 45 patients with AS. Results Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p&amp;lt;0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: i) TGF-b (r=0.72, p&amp;lt;0.001) and collagen (r=0.73, p&amp;lt;0.001) as markers of fibrosis; ii) NF-kB (r=0.36, p&amp;lt;0.01) and myocardial IL-6 (r=0.68, p&amp;lt;0.001) as markers of inflammation: iii) SOD2 (r=-0.38, p&amp;lt;0.006) as a marker of oxidative stress; iv) GLUT4 (r= 0.33, p&amp;lt;0.02) and PPAR-a (r=0.36, p&amp;lt;0.01) as markers of cardiac metabolism (Figure 1). Conclusion In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress. The hyper-expression of the SGLT2 gene and protein in patients with LF-LG might pave the way for using SGLT2-Is in this subset population, with the potential to improve the outcomes of AVR and reduce the likelihood of re-hospitalization within one year.Figure 1

Beneficial effects of the SGLT2 inhibition on oxidative skeletal muscle in infarcted rats

Abstract Introduction Metabolic, morphological, and biochemical changes in skeletal muscle are common in chronic heart failure patients. Despite the cardioprotective effects of sodium-glucose co-transporter 2 (SGLT2) inhibition in heart failure, the impact of this drug on skeletal muscle remains poorly understood. This study investigated the effects of SGLT2 inhibitor empagliflozin (EMPA) on the soleus muscle of rats with myocardial infarction (MI)-induced heart failure. Methods One week after MI induction, male Wistar rats were divided into Sham (n=10), Sham+EMPA (n=12), MI (n=10) and MI+EMPA (n=09) groups. EMPA was added to rat chow (5 mg/kg/day) for 12 weeks. Cardiac remodeling was evaluated by echocardiogram. Enzymatic activity and oxidative stress marker concentrations were assessed by spectrophotometry; protein expression was evaluated by Western blotting. After histological analysis of the left ventricle (LV), only rats with MI greater than 35% of total LV area were included in the study. Statistical analysis: ANOVA and Tukey or Kruskal–Wallis and Dunn and t test; p&amp;lt;0.05. Results Infarction size did not differ between groups. Infarcted groups had larger LV systolic and diastolic diameters, LV diastolic area (Sham 47±7.1; Sham+EMPA 48±4.5; MI 100±16.1*; MI+EMPA 85±10.1#† mm2; p&amp;lt;0.05: * vs Sham; # vs Sham+EMPA; † vs MI), and left atrial diameter (Sham 5.62±0.2; Sham+EMPA 5.65±0.3; MI 7.69±1.3*; MI+EMPA 6.85±0.9#† mm; p&amp;lt;0.05: * vs Sham; # vs Sham+EMPA; † vs MI); and lower LV posterior wall shortening velocity and ejection fraction than control groups. Echocardiographic changes were attenuated in MI+EMPA compared to MI. Other results are shown in Picture 1. Conclusion SGLT2 inhibitor empagliflozin attenuates infarction-induced cardiac remodeling in rats. Empagliflozin prevents increase in oxidative stress, modulates protein turnover by IGF-1 pathway, and attenuates morphological and biochemical changes in the soleus muscle of infarcted rats.

Risk stratification for a primary prevention ICD: Performance of the MADIT-ICD Benefit Score in contemporary real world patients

Abstract Background We have recently developed the MADIT-ICD Benefit Score to improve risk stratification for primary implantable cardioverter defibrillator (ICD) implantation by assessing the competing risk of life-threatening ventricular tachyarrhythmia (VTA) vs. non-arrhythmic mortality based using simple clinical variables. Patients with a MADIT-ICD Benefit Score of &amp;lt; 50 are more likely to experience non-arrhythmic mortality than life-threatening VTA, and therefore derive limited benefit from a prophylactic ICD. Purpose We aimed to provide data on the performance of the MADIT-ICD Benefit Score in a real world population, comprising patients with HFrEF and either ischemic or nonischemic cardiomyopathy (ICM/NICM) who are treated with contemporary guideline-directed medical therapy (GDMT). Methods The study population comprised 2875 patients who were implanted with a primary prevention ICD and prospectively followed in a large tertiary healthcare system (the University of Rochester Medical Center, including 3 affiliated hospitals in Upstate New York) between 2017 through 2023. Arrhythmic events were captured from device interrogation data, which were blindly adjudicated by 2 electrophysiologists. Results Among the 2875 study patients, mean age was 62 ± 15 years, 1265 (44%) were women, and 1667 (58%) had ICM. Guideline-directed medical therapies, including angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, angiotensin receptor/neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose transport protein 2 (SGLT2) inhibitors, were prescribed to 43%, 36%, 96%, 67% and 32% of study patients, respectively. The 2-year cumulative incidence of VTA, after accounting for the competing risk of death, was 19% vs. 11% in patients with a Score of ≥50 vs. &amp;lt;50, respectively (p&amp;lt;0.001; Figure 1A). Findings regarding ICD shocks were consistent (8% vs. 4%, respectively, p&amp;lt;0.001; Figure 1B) The rate of VTA events at 4 years was directly correlated with increasing quartiles of the MADIT-ICD Benefit Score, while the corresponding rates of non-arrhythmic mortality were inversely correlated with score quartiles (Figure 1C). A similar direct correlation with increasing Benefit Score quartiles was observed when the endpoint of ICD shocks was assessed (Figure 1D). Accordingly, the benefit of the ICD (calculated as the difference between predicted rates of VTA/shock events and corresponding rates of non-arrhythmic mortality) was attenuated with decreasing quartiles of the MADIT-ICD Benefit Score (Figures 1C and 1D; right column). Conclusions We show good performance of the MADIT-ICD Benefit Score in a large cohort of real world ICD recipients who are treated with contemporary GDMT. These data support the use of the MADIT-ICD Benefit Score for improved risk stratification and for shared decision-making in contemporary candidates for a primary prevention ICD.

Optimizing aldosterone receptor antagonist therapy by sodium zirconium cyclosilicate in heart failure - OPRA-HF trial

Abstract Background Heart failure remains a significant health burden, characterized by disabling symptoms and mortality rates comparable to cancer. Mineralocorticoid antagonists (MRAs), pivotal in treating heart failure with reduced ejection fraction (HFrEF), are underutilized due to concerns of hyperkalemia. Sodium Zirconium Cyclosilicate (SZC) enables optimized MRA therapy by reducing hyperkalemia. However, prospective studies on the efficacy and safety of SZC in patients with HFrEF and high hyperkalemia risk are lacking, particularly in the context of contemporary heart failure quadruple-therapy including angiotensin receptor neprilysin inhibitor (ARNI) and Sodium-Glucose Transport Protein 2 (SGLT2) Inhibitors. Purpose The OPRA-HF trial aims to assess the efficacy and safety of SZC in optimizing MRA treatment in symptomatic patients with HFrEF with risk for hyperkalemia on top of optimal guideline-directed medical therapy including ARNI and SGLT2 Inhibitors. Methods This investigator-initiated multicentred, randomized, placebo-controlled, and double-blinded trial include patients with HFrEF on suboptimal MRA treatment due to (1) history of hyperkalemia due to MRA, or (2) risk of hyperkalemia due to reduced renal function (eGFR 30-45 ml/min/m2) and current potassium 4.5-5-0 mmol/L. Patients undergo a Run-In phase with SZC, initiating or up-titrating MRA to target doses for 4-7 weeks and SZC was initiated in those patients that became hyperkalemic (K+&amp;gt;5 mEq/L. Those normokalemic and tolerating MRA ≥ 25 mg daily or at least 25 mg dose increase vs before run-in were randomized to SZC (5g or 10g) or placebo for 6 months. Study is powered to randomize 110 patients. Primary outcomes include maintaining daily MRA dose ≥ 25 mg or dose increase by 25 mg with normal potassium levels without rescue therapy. Secondary outcomes include evaluating the safety and tolerability of SZC as well as impact of SZC on quality of life. Results In this ongoing trial, so far 40 patients have been randomized. Of these, mean age was 74.3 years, 88.9% men. Most patients had ischemic etiology (54.2%), 36.1% had diabetes mellitus, 52.8% had hypertension.n. At screening 94.4% had beta-blockers, 35% ACEI/ARB, 60% ARNI and 72.2% had SGLT2 inhibitors, 33.3% had no MRAs and 35,6% of patients had less than 25 mg MRA daily,62,2% had 25 mg MRA daily, mean p-potassium was 4.7+0.4 mmol/L, and eGFR was 57.3 ml/min/1.73m². After run-in, 85.2% were on 50 mg MRA daily. A substantial number (51.2%) of eligible patients with previous hyperkalemia had Run-In failure as they now successfully tolerated target dose of MRA at 50 mg daily without recurrent hyperkalemia. SZC dosing was 5g once daily in 78.9% of patients. Conclusion This ongoing trial will provide evidence for the use of SZC to optimize MRA treatment in contemporary HFrEF patients. Preliminary findings suggest SZC effectively maintains normokalemia, enabling MRA optimization, potentially improving patients’ otcome.

Effect of empagliflozin on no-reflow in patients with st elevation myocardial infarction undergoing primary percutaneous coronary intervention

Abstract Background Primary percutaneous coronary intervention (PPCI) restores myocardial tissue perfusion successfully in over 90 % of ST-elevation myocardial infarction (STEMI) patients .However there remains a small proportion of patients who exhibit no-reflow.(1) Empagliflozin is a sodium glucose co-transporter 2 (SGLT2) inhibitor that acts as a powerful anti-oxidant and has beneficial effects on endothelial function and reducing burden of ischemia in-vitro.(2) Aim and Objectives: To Assess the effect of Empagliflozin preloading in non-diabetic STEMI patients before PPCI on procedural, in-hospital outcomes and short-term Major Adverse Cardiovascular events (MACE) in a single tertiary center. Patients and Methods: The study was carried out on 200 non-diabetic STEMI patients presenting to our university hospital within the first 8 hours of symptom onset. Patients were randomised into 2 groups , the intervention group received 10mg Empagliflozin before PPCI with the standard medical therapy while the control group received only the standard medical therapy. Patients were assessed for demographic data, risk factors, procedural outcomes, clinical and in-hospital outcomes, and short-term MACE up to 1 month. Results: Our study found a significant difference between the intervention and control groups regarding contrast volume with a mean of 131 ml in the intervention group and 144 ml in control group with a p value of 0.009, incidence of no-reflow with 34.5% in the control group and only 18.2% in the intervention group and a p value of 0.014 and myocardial blush grade (MBG) were 84.1% of the patients in intervention group had MBG III after PCI while only 65.5% of the patients in the control group showed the same results with a p value of 0.019. Also, there was a significant difference in St-segment resolution post PCI as 59.1% of patients in the intervention group had complete ST segment resolution and only 39.1% of the patients in the control group had complete resolution with a p-value of 0.027, and total MACE in the first month which affected 44.8% of the patients in the control group and only 28.4% of those in the intervention group with a p-value of 0.024. Conclusion Our study showed that pre-loading of STEMI patients with Empagliflozin resulted in improvement in procedural outcomes, decreasing the incidence of coronary no-reflow, improvement in patient’s course during hospital stay and short-term MACE. Improvement in MACE was mainly due to reduced HF hospitalisations and anginal symptoms.

Impact of SGLT2 inhibitor dapagliflozin on myocardial protein profile in rats with long-standing Type 1 diabetes mellitus

Abstract Background Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on the cardiovascular system in diabetes mellitus (DM) patients. However, as most trials have focused on Type 2 DM, the impact of SGLT2 inhibitors on Type 1 DM remains unclear. Objective To investigate the effects of long-term treatment with SGLT2 inhibitor dapagliflozin on the left ventricular (LV) proteome in Type 1 DM rats. Methods Male Wistar rats were divided into three groups: Control (C, n=7); Diabetes (DM, n=6); and Diabetes treated with Dapagliflozin (DM+DAPA, n=8) for 30 weeks. Diabetes was induced by streptozotocin (40 mg/kg). Dapagliflozin was added to chow at 5 mg/kg/day. Label-free mass spectrometry was used to assess LV proteome using a nanoAcquity UPLC-Xevo QTof MS system and ProteinLynx Global Server (PLGS) software. Cytoscape software, Cluster Marker, and Cluego plugins were used for bioinformatic analysis. Statistical analysis: ANOVA and Tukey or Kruskal-Wallis and Dunn. Results Dapagliflozin increased body weight (C 574±43; DM 339±31*; DM+DAPA 413±30*# g; p&amp;lt;0.05: * vs C; # vs DM) and reduced glycemia [C 108 (101–111); DM 554 (529–562)*; DM+DAPA 343 (237–416)*# mg/dL; p&amp;lt;0.05: * vs C; # vs DM]. One rat died in C and two in DM+DAPA. A total of 252 differentially expressed proteins were identified. Most proteins identified in the networks were downregulated in DM vs C and upregulated in DM+DAPA vs DM. Six proteins related to energy metabolism (Atp5j, P21571; CKm, P00564; Ak1, P39069; Atp5h, P31399; Mdh1, O88989; and Idh2, P56574), four involved in myocyte excitation-contraction (Act1, P68065; Casq2, P51868; SERCA1, Q64578; and SERCA2a, P11507), and two associated with oxidative stress (Sod1, P07632; and Sod2, P07895) were upregulated in DM+DAPA x DM. Comparing DM with C, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to gap junction (25.6%), necroptosis (25.6%), and fatty acid degradation (25.6%), and for downregulated proteins was related to Alzheimer disease (27.3%), cardiac muscle contraction (25%) and glycolysis/gluconeogenesis (13.6%). Comparing DM+DAPA with DM, the KEEG Pathway with the highest percentage of gene associations for upregulated proteins was related to Parkinson disease (18.3%), cardiac muscle contraction (14.2%), citrate acid cycle (9.47%), necroptosis (8.88%), and cGMP-PKG signaling (7.10 %), and for downregulated proteins was related to ketone bodies synthesis and degradation (100%). Conclusion Dapagliflozin is safe and prevents changes in the expression of proteins related to energy metabolism, cardiac muscle contraction, and oxidative stress in Type 1 diabetes mellitus rats. These results offer new insights into the cardioprotective mechanisms of dapagliflozin in Type 1 diabetes mellitus.

Identification and optimisation of a risk stratified cohort of patients with type 2 diabetes through the delivery of a enhanced pharmacist-led service

Abstract Introduction Cardio-renal metabolic (CRM) diseases are each associated with significant morbidity and mortality, and due to their shared pathology, the benefit of managing these diseases holistically is becoming increasingly evident. The East Belfast Federation practices have sought to review patients living with type 2 diabetes (T2D), prioritising those not meeting their 3 Treatment Targets (3TT, HbA1c, blood pressure [BP] and cholesterol) to optimise treatment through a pharmacist-led model of care. Aims and Objectives 1. Improve adherence to latest update of NICE T2D [NG28, 2022], with a focus on patients with Cardiovascular Disease (CVD) &amp; Chronic Kidney Disease (CKD). 2. Upskill diabetes teams, to create a legacy effect and ensure improved holistic management will continue beyond the project period. 3. Use a clinical audit tool to identify, stratify and optimise T2D patients not meeting their 3TTs. 4. Improve identification, coding and recall of patients with non-diabetic hyperglycaemia (NDH) as per QOF Indicator NDH001NI [QOF 2022/23]. 5. Enhanced focus on review of sulphonylureas (SU) in relation to frailty and risk of hypoglycaemia [Strain, 2021]. Method Patients not meeting their 3TTs (HbA1c&amp;gt;58 mmol/mol, BP&amp;gt;140/80mmHg, total cholesterol&amp;gt;5mmol/L) were identified from October 2022 to July 2023. Primary care based clinics created which we tailored to the specific needs of the practices with a focus on optimising patients with CVD &amp; CKD co-morbidities. Dedicated specialist education and clinical support was provided to existing diabetes teams in CRM patient management. Additional searches were created and patients identified to review patients experiencing NDH and on a SU. Results At 9 months from baseline, there was a statistically significant improvement of 8.9% in patients achieving all 3TTs (n=373, P=0.013). This was accompanied by an increase in the number of patients optimised for CV risk reduction, with a 39% and 42% increase in patient receiving sodium glucose co-transporter-2 (SGLT2) inhibitors (n=542) and Glucagon-like peptide-1 receptor agonists (GLP1RA) (n=190), respectively. A 5.5% (n=28) reduction in the number of patients on a SU was observed, as well as a 44% (n=76) increase in the number of referrals into the Diabetes Prevention Programme (DPP). 151 statins and 51 BP medications were started/optimised. Discussion and Conclusion The project further exemplifies the feasibility of a pharmacist-led T2D service in a primary care setting. In addition to improvement in established T2D markers, the role promoted collaboration and facilitated best-practice sharing across multiple diabetes teams. This approach allows for more co-ordinated care for patients who may otherwise be referred to multiple specialists, which often results in fragmented care. Future work should focus on promoting CRM protection as early as possible to reduce disease progression and improve outcomes.Number of patients on antidiabetic meds% attainment of 3TT

Effect of Dapagliflozin on health-related quality of life in patients with heart failure: a meta-analysis of Randomized Controlled Trials

Abstract Introduction Dapagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, reduces the risk of cardiovascular mortality and hospitalization for heart failure among individuals with chronic heart failure with reduced (HFrEF) or preserved ejection fraction (HFpEF). The effect of dapagliflozin on symptoms, physical capacity and quality of life is still unclear in this population. Purpose To investigate the effects of dapagliflozin on symptoms and health-related quality of life improvement in patients with chronic heart failure. Methods We systematically searched PubMed, Embase and Cochrane Central databases for randomized controlled trials (RCTs) comparing dapagliflozin to placebo in patients with chronic heart failure. We pooled mean differences (MD) and 95% confidence intervals (CI) with a random-effects model for continuous outcomes. Subgroup analyses were performed by reduced or preserved ejection fraction (EF). The outcomes analyzed were change in Kansas City Cardiomyopathy Questionnaire (KCCQ) score and six-minute walk test (6MWT). Results Five RCTs with 6,238 patients were included. Of these, 5,410 (86.7%) presented a reduced EF and 2,724 (43.65%) had diabetes. There was a statistical significant improvement in total symptoms score (KCCQ-TSS) (MD=3.08; 95% CI 2.14-4.02; p&amp;lt;0.00001; I2=0%; Fig.1A) and in physical limitation score (KCCQ-PLS) (MD=3.91; 95% CI 1.66-6.17; p=0.0007; I2=0%; Fig1B) when dapagliflozin was compared to placebo. Subgroup analyses showed that the KCCQ-TSS score were significant higher in patients treated with dapagliflozin when compared to placebo in HFrEF (MD= 2.98; 95% CI 1.96-.99; p&amp;lt;0.00001; I2=0%; Fig1A) and HFpEF group (MD=3.73; 95% CI 1.16-6.30; p=0.004; I2=0%; Fig1A). The KCCQ-PLS score had a significant increase after dapagliflozin treatment when compared to placebo in participants with HFrEF (MD=4.36; 95% CI 0.72-8.00; p=0.02; I2=0%; Fig1B) and HFpEF (MD=3.64; 95% CI 0.76-6.51; p=0.01; I2=0%; Fig1B). There was no significant difference in 6MWT in dapagliflozin versus placebo group (MD=5.78; 95% CI -0.48-12.03; p=0.07; I2=0%; Fig.2). Conclusions Dapagliflozin improves health-related quality of life by reducing symptoms and physical limitation in patients with HFrEF and HFpEF.

Effect of empagliflozin on epicardial adipose tissue volume in patients with type 2 diabetes, or prediabetes, and heart failure with reduced ejection fraction (SUGAR-DM-HF)

Abstract Background Epicardial adipose tissue (EAT) is postulated to be linked to the pathophysiology of heart failure with reduced ejection fraction (HFrEF), acting both as a biomarker and a potential therapeutic target. Investigating changes in EAT volume following treatment with sodium-glucose cotransporter 2 (SGLT2) inhibitor could provide valuable mechanistic insights. Purpose This posthoc substudy of the SUGAR-DM-HF trial aimed to assess the effect of the SGLT2 inhibitor empagliflozin on EAT volume. Methods Within a multicentre, randomised, double-blind, placebo-controlled trial, the effects of empagliflozin were evaluated in patients with HFrEF (New York Heart Association functional class II-IV, left ventricular ejection fraction (LVEF) ≤40%), and type 2 diabetes or prediabetes. Patients with atrial fibrillation/flutter were excluded to avoid image degradation. Patients were randomly assigned 1:1 to empagliflozin 10mg daily or placebo. EAT volume was quantified using cardiovascular magnetic resonance (CMR) cine imaging at baseline and week 36, and reported as: (a) total EAT volume (mL); (b) EAT volume indexed to body surface area (mL/m2); (c) % change from baseline. Observers were blinded to subject identification, scan date, clinical data, and randomization arm. Scans with major artefacts were not analysed. Results One hundred five patients were randomly assigned: mean age 68.7 (SD, 11.1) years, 77 (73.3%) male, 82 (78.1%) diabetes and 23 (21.9%) prediabetes, mean LVEF 32.5% (9.8%). Baseline EAT volume was available in 101 patients (median [IQR] 85 [67-104] mL and 41 [34-52] mL/m2). Paired baseline and 36-week EAT volume was available in 90 patients. Higher baseline total EAT volume was associated with male gender, higher body mass index, coronary artery disease, elevated serum creatinine, higher left ventricular end-diastolic volume, and higher left ventricular mass (TABLE). EAT volume changed by -2.7 mL / -1.3 mL/m2 / -3.1% in the empagliflozin group versus 0.3 mL / 0.3 mL/m2 / 1.5% in the placebo group (between-group difference -3.4 mL, 95% CI -6.7 to -0.1; p=0.045 and -1.7 mL/m2, 95% CI -3.4 to -0.04; p=0.045) at 36 weeks (FIGURE). The beneficial reduction in left ventricular end-systolic volume indexed to body surface area observed with empagliflozin treatment was not modified by baseline total or indexed EAT volumes (p interaction=0.31 and 0.45, respectively). Conclusion Empagliflozin treatment significantly reduced EAT volume. This may represent an additional benefit of SGLT2 inhibition in HFrEF.

Empagliflozin: unlocking new potentials in heart failure decongestion

Abstract Background Managing acute heart failure (AHF) remains a formidable challenge in cardiology, primarily due to the limitations of conventional decongestive therapies. This study explores the efficacy of Empagliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, in decongestion management for AHF. Methods Conducted in a tertiary care setting, this prospective cohort study involved 450 patients, divided equally into an Empagliflozin group and a control group receiving standard care. The study assessed changes in body weight, clinical congestion scores, hematocrit levels, and NT-proBNP levels as primary outcomes over a period of 90 days. Safety and adverse events related to Empagliflozin were also monitored. Results Empagliflozin led to a significant reduction in body weight (mean difference at Day 15: −1.95 kg, P&amp;lt;0.0001), and clinical congestion scores (mean difference at Day 15: −0.35, P=0.0050). Hematocrit levels increased significantly (mean increase at Day 15: 1.65%, P&amp;lt;0.0001), and NT-proBNP levels showed a more substantial decrease in the Empagliflozin group compared to the placebo. Safety profiles were consistent with previous studies, showing no significant increase in adverse events. Conclusion Empagliflozin demonstrates a substantial improvement in decongestion management in AHF patients, offering a promising alternative to traditional therapies. The findings indicate potential broader applications in heart failure management and support the need for updated clinical guidelines incorporating Empagliflozin as a therapeutic option in AHF.