SGLT2 Inhibitors Research Articles

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.

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.

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.

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.

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.

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.

Changes in N-terminal pro b-type natriuretic peptide according to SGLT2 inhibitor utilization patterns in patients hospitalized for decompensated heart failure: a prospective cohort study

Abstract Introduction Sodium-glucose cotransporter-2 (SGLT2) inhibitors have found success in treating patients with chronic heart failure (HF) across the entire spectrum of left ventricular ejection fraction (EF). Their benefits may also extend to patients with acute HF decompensation, as they may aid effective decongestion. Purpose This study aims to present the various patterns in changes of N-terminal pro b-type natriuretic peptide (NT-proBNP) according to SGLT2 inhibitor use in patients hospitalized for acute HF decompensation. Methods In this prospective cohort study, we enrolled consecutive patients hospitalized for HF decompensation during a 4-month period in a cardiology department. Prior medical history and cardiovascular risk factors were recorded. The patterns in SGLT2 inhibitor use were noted and patients were classified into three groups; Group 1 (No SGLT2 inhibitor use/Discontinuation), Group 2 (Prior SGLT2 inhibitor use and continuation), and Group 2 (SGLT2i-naïve and initiation). Categorization according to left ventricular (EF) to HF with reduced EF (HFrEF), HF with mildly reduced EF (HFmrEF), and HF with preserved EF (HFpEF) was also performed. Moreover, estimated glomerular filtration rate (eGFR) was used as an estimate of renal function. Results In this analysis, 159 patients were included (median age: 79 years old, male sex: 64.8%, median duration of hospitalization: 6 days). In this population, 67.9% of the patients were not receiving a SGLT2 inhibitor on admission. Concerning demographic and clinical variables (Figure 1), there were no major differences in age, sex distribution, history of diabetes mellitus, dyslipidemia, and atrial fibrillation, as well as in renal function. Group 2 patients had a lower prevalence of arterial hypertension compared to Group 3 (36.6% vs. 52.6%, p&amp;lt;0.05). Moving to the changes in NTproBNP (Figure 2), we observed that patients who did not use SGLT2 inhibitors and did not initiate them during hospitalization had negligible changes in NTproBNP, either as an absolute change (Group 1: 506 (8792) pg/ml vs. Group 2: -5610 (9461) pg/ml vs. Group 3: -3602 (4409) pg/ml, p=0.001) or as percentage change (Group 1: -2.1 (63.4) % vs. Group 2: -30.3 (39.0) % vs. Group 3: -38.3 (41.5) %, p=0.001), compared to the rest of the study population who were already taking SGLT2 inhibitors or initiated them during hospitalization. Conclusion In this study we found NTproBNP, a widely used biomarker of congestion and prognosis in HF, was significantly reduced in decompensated HF patients receiving SGLT2 inhibitors, with the greatest change being observed in those being treatment-naïve prior to admission. These findings further highlight the role of this drug class even in the acute phase of the disease.Figure 1Figure 2

Real-life data on the tolerability of SGLT2 inhibitors in elderly patients with heart failure

Abstract Introduction Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have demonstrated their effectiveness in improving the prognosis of heart failure. However, there is some hesitation in clinical practice to prescribe them to elderly patients due to a lack of long-term safety data. The SafeGLT2 study aims to evaluate the tolerance of SGLT2i in elderly patients with heart failure in real-life settings. Methods This is a prospective study conducted in acute geriatric units in the Île-de-France region between February 2020 and May 2023. All patients admitted for acute heart failure (AHF), aged 75 years and older, were included. The diagnosis was confirmed by an expert committee, and patients were followed for one year. Treatments were recorded upon admission and discharge, along with demographic characteristics and medical history. SGLT2i tolerance data were collected and analyzed, including renal insufficiency, hypovolemia, genital infections, urinary infections, hypoglycemia, diabetic ketoacidosis, fractures, amputations, etc. A comparison of tolerance data between heart failure patients treated with SGLT2i and those not receiving SGLT2i was performed. Results 288 patients were included in the study with a mean age of 88 years, 53% (n=153) were female, and a median Charlson Comorbidity Index (CCI) of 8.77 [2.71]. 44.1% (n=127) of patients had neurocognitive disorders, 39.6% (n=114) were malnourished, 32.6% (n=94) were fallers, 53.8% (n=155) had renal insufficiency (eGFR &amp;lt; 60 ml/min), and 11.5% (n=33) lived in institutions. A total of 33% (n=95) were treated with SGLT2i upon discharge. No serious adverse effects were found in this very frail population receiving SGLT2i compared to the group not receiving SGLT2i (severe hypotension, hypovolemia, ketoacidosis, hypoglycemia, fracture, amputation). Beneficial effects on renal function (improvement of renal function at 6 months) were observed in the SGLT2i group despite a temporary decrease in glomerular filtration rate of less than 30% after SGLT2i initiation. However, a statistically significant increase in urinary tract infections (16.8% vs 4.15%), genital infections (12.6% vs 1.5%), and constipation (10% vs 1%) was found in the SGLT2i group compared to the group without SGLT2i. Conclusion These data indicate that SGLT2i are well tolerated in very elderly frail heart failure patients. However, the occurrence of urogenital infections appears to be more frequent in this population and requires particular surveillance.

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 &amp;gt;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 &amp;gt;40%.Figure 1

Association of sodium-glucose cotransporter-2 inhibitor with regression of coronary plaque burden

Abstract Background Sodium-glucose cotransporter-2 inhibitor (SGLT2i), as a novel oral hypoglycemic therapy of type 2 diabetes mellitus (T2DM), has been proved to benefit cardiac function. However, it remains unknown whether SGLT2i has an impact on coronary plaque characteristics. Purpose The aim of this study was to investigate whether SGLT2i was able to improve coronary plaque composition, burden and inflammation [i.e., fat attenuation index (FAI)] using series coronary computed tomography angiography (CCTA) images among T2DM patients with angina pectoris. Methods T2DM patients presenting with angina pectoris admitted at our center were screened. Eligible patients were those underwent first CCTA within 3 months prior to initiating SGLT2i therapy, and repeated CCTA beyond 6 months after the first CCTA. Those patients not treated with SGLT2i underwent likewise longitudinal CCTA tests were propensity score matching in a 1:1 ratio using age, sex and CCTA time interval. Routine CCTA images were assessed for coronary plaque characteristics using dedicated softwares. Paired or unpaired Student’s t test or Mann–Whitney U test were used for comparing coronary plaque characteristics between series CCTA and patients with or without SGLT2i. The relationships between SGLT2i and changes of plaque characteristics was examined using logistic regression analysis. Results After propensity score matching, a total of 196 T2DM patients with angina pectoris were included (mean age, 60.4±9.2 years; male, 69.9%; SGLT2i treatment, 50%). Time interval between baseline and the last CCTA examinations was 400 (343,496) days. In the SGLT2i group, the non-calcified plaque burden [(39.86±14.30)% vs. (36.84±13.86)%, p=0.002)] and low attenuation non-calcified plaque burden (6.62 [4.11,10.13]% vs. 5.78 [3.40,9.28]%, p=0.042) were significantly decreased between two CCTA images. Whereas, in the non-SGLT2i group, there was no difference with regard to non-calcified and low attenuation non-calcified plaque burden between two CCTA images (all p&amp;gt;0.05). Moreover, changes of total plaque burden and non-calcified plaque burden were higher in the SGLT2i group than the non-SGLT2i group (all p&amp;lt;0.05). Importantly, SGLT2i was associated with total plaque volume (odd ratio=0.594, p=0.024) and non-calcified plaque volume regression (odd ratio=0.619, p=0.042) after adjusting for confounding factors. Conclusion SGLT2i significantly regresses coronary plaque burden, in particularly non-calcified plaque. These findings might explain the observed cardio-protective effect of SGLT2i in large trials.

Modern heart failure treatment is superior to conventional treatment across the left ventricular ejection spectrum: Real-life data from the Swedish Heart Failure Registry 2013-2020

Abstract Background Heart failure (HF) is a clinical syndrome characterized by high mortality and morbidity. In 2016, Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor (ARNI), was recommended as a new treatment option for HF in patients with HFrEF. In the 2021 European Society of Cardiology guidelines for treatment of HFrEF patients Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were introduced because they demonstrated significantly reduced HF events or cardiovascular (CV) mortality. Since ARNI and SGLT2i were introduced to treat HF, its therapeutic regimen has modernized from previous treatment with beta-blocker (BB) and angiotensin-converting enzyme inhibitor (ACEi)/angiotensin II receptor blocker (ARB) with mineralocorticoid receptor antagonist (MRA) as added-on in HF with reduced ejection fraction (HFrEF). Purpose This study is aimed to compare effectiveness of modern therapy including ARNI and SGLT2i with conventional heart failure treatment. Conventional HF treatment includes (BB, ACEi/ARB, with or without MRA) and modern heart failure treatment (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i) in real-world. Methods This observational study (2013-2020), using the Swedish HF Registry, involved 20,849 HF patients. Patients received either conventional (BB, ACEi/ARB, with/without MRA, n=20,140) or modern (BB, ACEi/ARB, MRA, SGLT2i or BB, ARNI, MRA with/without SGLT2i, n=709) treatment at the index visit. The endpoints were all-cause and cardiovascular (CV) mortality. Results Modern HF therapy was associated with a significant 28% reduction in all-cause mortality compared to conventional HF treatment (adjusted HR [aHR]: 0.72 (95% CI 0.54 - 0.96), p=0.024), and had 33% reduced all-cause mortality (aHR: 0.67 (95% CI 0.48 - 0.94), p=0.019) within 2 years of index registration. Similarly, modern HF therapy was associated with a significant 62% reduction in CV mortality compared to conventional HF treatment (aHR: 0.38 (95% CI 0.21 - 0.68), p=0.0013). In addition, we found a 58% reduced CV mortality (aHR 0.42 (95% CI 0.22 - 0.79), p=0.0067) within 2 years of index registration. In the propensity score 1:1 matched cohort in which ARNI was included in the matching procedure, i.e., no ARNI was used in any of the two treatment groups and the effect of SGLT2i was the target assessment. The results were associated with a statistically significant risk reduction of 42% in all-cause mortality in the modern HF treatment group compared to the conventional treatment group (aHR: 0.58 (95% CI 0.36 - 0.94), p=0.028), and a 49% (aHR: 0.51 (95% CI 0.29 - 0.89), p=0.018) risk reduction within 2 years of index registration. Conclusion This study demonstrates that modern HF therapy in a real-world Swedish HF population is associated with a statistically significant risk reduction in all-cause and CV mortality, regardless of EF, sex, age, eGFR, and etiology of HF compared to conventional HF therapy.Central Illustration

Effects of glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter-2 inhibitors and their combination on mitochondrial-derived peptide-c and on markers of neurohumoral activation

Abstract Background/Introduction Type-2 diabetes mellitus (T2DM) is associated with increased prevalence of cardiovascular disease. Purpose We investigated the effects of insulin, glucagon like peptide-1 receptor agonists (GLP-1RA), sodium-glucose cotransporter-2 inhibitors (SGLT-2i) and their combination on mitochondrial-derived peptide-c (MOTS-c), N-terminal pro B-type natriuretic peptide (NT-proBNP), growth differentiation factor (GDF)-15, oxidant and antioxidant biomarkers and cardiovascular function of T2DM patients. Methods A total of 160 T2DM patients were randomized to insulin (n = 40), liraglutide (n = 40), empagliflozin (n = 40) or their combination (GLP-1RA+SGLT-2i) (n = 40) as add-on to metformin. We measured at baseline, at 4 and at 12 months of treatment: a) plasma levels of MOTS-c, NT-proBNP and GDF-15, b) thiobarbituric acid reactive substances (TBARS), as an oxidant biomarkers, and 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS), as an antioxidant biomarker, and c) global left ventricular longitudinal strain (GLS) and global work index (GWI) using speckle-tracking imaging. Results Twelve months after treatment, treatment with SGLT-2i and GLP-1RA+SGLT-2i improved MOTS-c (14.89 ± 11.27 vs. 7.26 ± 4.21 ng/mL, p=0.009, 6.49 ± 3.91 vs. 5.6 ± 3.38 ng/mL, p=0.029, respectively), while treatment with insulin and GLP-1RA had a neutral effect on this biomarker (p &amp;gt; 0.05; Table). GLP-1RA, SGLT-2i and their combination showed a greater reduction of NT-proBNP (-43.1% vs. -54.2% vs. -56.9% vs. -14.7%; Figure) and GDF-15 (-14.8% vs. -15.2% vs. -16.1% vs. -0.9%) than insulin (p &amp;lt; 0.05 for all comparisons), despite the fact that all patient achieved adequate glycemic control. GLP-1RA or GLP-1RA+SGLT-2i provided a remarkable reduction of TBARS and increase of GLS and GWI compared to insulin or SGLT-2i (p &amp;lt; 0.05). In all patients, at 4 and at 12 months, the percentage reduction of NT-proBNP was associated with the improvement of TBARS, GLS and GWI (p &amp;lt; 0.05). The percentage reduction of GDF-15 was correlated with the increase of ABTS and with the improvement of GLS at 4 and 12 months (p &amp;lt; 0.05). In SGLT-2i group, the percentage increase of MOTS-c was related with the percentage reduction of GDF-15 (r = 0.81, p = 0.005) at 12 months. Conclusions Twelve-month treatment with GLP-1RA, SGLT-2i and their combination resulted in reduction of cardiac biomarkers in parallel with a greater decrease of oxidative stress than insulin in T2DM. SGLT-2i appears more effective in the improvement of MOTS-c and markers of neurohumoral activation.TableFigure

Effect of sodium-glucose cotransporter-2 inhibitor (SGLT2-i) in patients with LVAD: a systematic review and meta-analysis

Abstract Introduction Sodium-glucose cotransporter-2 inhibitor (SGLT2-i) have been shown to reduce risks of clinical events in patients with heart failure (HF). However, data on the use of SGLT2-i in patients with left ventricular assist devices (LVAD) are scarce. We thought to assess the efficacy and safety of SGLT2-i in patients with LVAD Methods A systematic search was done in PubMed, Scopus, Web of Science, Embase, and Cochrane from inception to December 2023. We used all relevant words for "SGLT2-i" and "LVAD" to search in databases and we included studies and published abstracts in peer-reviewed journals of studies assessed SGLT2-i in patients with LVAD. The efficacy and safety data were extracted across the studies. RevMan 5.4.1 was used for meta-analysis. Results Three studies and eight abstracts totaling 209 patients using SGLT2-i were included. Empagliflozin, Dapagliflozin, and Canagliflozin were the used SGLT2-i across the included studies. SGLT2-i effectively decreased hemoglobin A1c (HbA1c) (Mean = -0.44, 95% CI [-0.79, -0.09], p = 0.01) and diuretic dose (Mean=-2.54, 95% CI [-3.56, 1.51], p&amp;lt; 0.00001) from baseline. No significant improvement was found for glomerular filtration rate (GFR), B-type natriuretic peptide (BNP), or mean pulmonary artery pressure (MPAP). Regarding safety, the pooled percentage of people with driveline infection was 9.33%, 95% CI [2.05, 16.60], p=0.01. Conclusion SGLT2-i effectively improves HbA1c and diuretic dose in patients using LVAD. Further randomized studies with a large number of participants may be warranted.

Sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide 1 receptor agonists and cancer mortality. A real-world registry

Abstract Background Sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1ra) reduce cardiovascular events through different mechanisms, nevertheless, their association with cancer remains unclear. Purpose We aim to compare the combined treatment (SGLT2i and GLP1ra) with monotherapy regarding hospitalization or/and death for cancer in a general population and a subgroup of patients with cardiovascular disease (CVD). Methods Retrospective observational study of patients who were prescribed SGLT2i, GLP1ra, or both drugs. Multinomial propensity score was performed in all the population and in a subgroup of patients with CVD (atrial fibrillation [AF], heart failure [HF], coronary artery disease [CAD], peripheral arterial disease [PAD], or cerebrovascular accident [CVA]). The following variables were included to adjust the three groups: Sex, Age, Obesity, diabetes mellitus (DM), high blood pressure (HBP), dyslipidemia (DLP), CAD, HF, AF, and CVA. The three primary outcomes were (i) hospitalization for any cancer, (ii) death for any cancer, and (iii) the combined event in the included population and the subgroup of patients with CVD. The multivariate Cox regression analysis determined the hazard rate (HR) of age, sex, risk factors, and treatment for each outcome. Results We included 14709 patients (11366 with SGLT2i, 1016 with GLP1ra, and 2327 with both treatments) from the treatment initiation. The subgroup with CVD included 4957 (33.7%) patients (Fig 1). After 33 months of median follow-up, the incidence of cancer events was similar between patients with and without CVD (3.4% or 3.7%, respectively). Sex (male) and age were the main risk factors for the 3 outcomes in both groups. Combined treatment and its duration had a protector role for cancer mortality regarding monotherapy with SGLT2i or GLP1ra in all population (HR [95%CI]) 0.2216 [0.106-0.459]; p&amp;lt;0.001 or 0.1928 [0.071-0.519]; p=0.001, respectively) (Fig 2a) and in the subgroup of patients with CVD (HR [95%CI]) 0.279 [0.078-0.994]; p&amp;lt;0.049 or 0.129 [0.024-0.668]; p=0.014, respectively) (Fig 2b), but these results were not found for the outcome of hospitalization for cancer. The combined therapy concerning SGLT2i and duration of treatment showed a protective role against the combined event (HR [95%CI]) 0.709 [0.521-0.967]; p=0.029) and (HR [95%CI]) 0.991 [0.983-0.999]; p=0.032) in the general population but not in the group of CVD. A higher survival rate for any cancer mortality was observed in those patients with the combined therapy respect to monotherapy (SGLT2i or GLP1ra) in the general population (Fig 2c) and the subgroup of patients with CVD (Fig 2d). Conclusions Initiation of combined therapy vs. monotherapy was associated with a lower rate of cancer mortality in the general population and patients with CVD. Future clinical trials and mechanistic studies will clarify the possible role of these drugs on carcinogenesis.Figure 1Figure 2

Potential hematopoietic effects of SGLT2 inhibitors in patients with cardiac amyloidosis

Abstract Introduction Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have been revealed to have potential hematopoietic effects in patients with heart failure (HF), leading to an improvement in clinical outcome. However, these benefits have not been studied in patients with cardiac amyloidosis (CA), despite CA often causing symptoms of heart failure (HF) and contributing to an iron-deficient state, which further complicates by limiting erythropoiesis and lowering haemoglobin and haemotocrit levels. We aimed to determine the potential of SGLT2i in improving haematological parameters and functional capacity (FC) in amyloidosis patients. Methods A prospective analysis was conducted to compare the effects of SGLT2i in a cohort of patients who received the best medical therapy (BMT) alongside SGLT2i (n=20), as opposed to patients receiving only BMT without SGLT2i (n=20). All of patients underwent blood testing and cardiopulmonary exercise testing (CPET) at baseline and after 6 months (IQR:5.0 – 6.0). Results The SGLT2i-based therapy resulted in a significant improvement and difference in hematological parameters upon follow-up assessment compared to the control group. In the SGLT2i group, the mean haemoglobin level increased from 13.3 g/dL to 14.5 g/dL, whereas in the control group, it decreased from 12.7 g/dL to 10.9 g/dL (P &amp;lt; 0.001). Furthermore, the haematocrit difference showed a significant increase in the SGLT2i group (+3.8%) compared to a decrease in the control group (-4.4%) (P &amp;lt; 0.001). Additionally, the iron status improved in the SGLT2i-treated group (+6.7 µg/dL) compared to a decrease in the control group (-14.9 µg/dL), although the difference was significant only with a p-value of 0.034. However, neither group demonstrated significant improvement nor regression in CPET parameters. The peak oxygen consumption (peak VO2, (ml/min)/kg) showed no significant change in either group (P = 0.286), as well as VE/VCO2 slope (P = 0.295). Conclusions Treatment with SGLT2i could be utilized in the treatment of patients with amyloidosis. This potential benefit in improving hematological parameters warrants further investigation and consideration in clinical practice.

Prognostic impact of SGLT2-inhibitor therapy on survival in patients with transthyretin amyloid cardiomyopathy

Abstract Background Sodium-glucose co-transporter 2 inhibitors (SGLT2i) significantly improve cardiovascular outcomes in patients with heart failure across the whole spectrum of ejection fraction. Recently published data indicates the safety and tolerability of SGLT2i therapy in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). However, there is a lack of evidence regarding the impact of SGLT2i therapy on clinical outcomes in those patients. Purpose This study aims to investigate the association between SGLT2i therapy and clinical outcomes in patients with ATTR-CM. Methods This is an analysis of a prospective registry conducted at an expert center for hypertrophic cardiomyopathies. We included all participants with a confirmed diagnosis of ATTR-CM, who were enrolled until December 2022. Prior and concomitant SGLT2i treatment was systemically assessed according to the patient interview and medical records. Patients’ outcomes were retrieved from local medical and health insurance records. Results We enrolled 116 patients, of whom 7 patients (6%) were treated with SGLT2i at inclusion and 44 patients (38%) were started on SGLT2i therapy during the observational period while 65 patients (56%) were SGLT2i-naïve. There were no significant differences in baseline characteristics between groups, as shown in the table. Median (interquartile range) age was 80 (76-82) years with 15% females. Median N-terminal pro-brain natriuretic peptide (NT-proBNP) was 2844 (1519-5033) pg/ml, median estimated glomerular filtration rate (eGFR) 58 (46-69) ml/min/1,73m2, and median troponin T 56 (34-83) pg/ml. During a median follow-up of 2.6 (1.8-3.7) years, 28 patients (24%) died, of whom 6 patients (5%) were in the treatment group and 22 patients (19%) in the control group. In univariate Cox-regression analysis, SGLT2i treatment was significantly associated with a lower mortality (HR 0.325, 95%CI 0.132-0.802, p=0.015). This association persisted after adjusting for age and sex (HR 0.347, 95%CI 0.139-0.867, p=0.023). However, when treatment initiation time was considered, the benefit did not remain statistically significant. No significant associations between SGLT2i treatment and worsening heart failure hospitalizations or cardiovascular death were observed. Conclusion In a prospective registry-based cohort of patients with ATTR-CM, SGLT2i therapy was associated with significantly better survival, with a potential treatment initiation time bias. These results suggest that SGLT2i may exert beneficial effects in patients with ATTR-CM and warrant a randomized controlled trial.

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

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 &amp;lt; 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.

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

All cause mortality in people with type 2 diabetes using SGLT-2 inhibitors compared to DPP4 inhibitors using the danish registries

Abstract Background The SGLT-2 inhibitors outcome trials such as EMPA-REG have had significant impact on the treatment and management of patients with type 2 diabetes. Using real world danish data simulating EMPA-REG criteria can demonstrate the efficacy of SGLT-2 in real world clinical settings. Aim The purpose of this study is to evaluate the efficacy of SGLT-2 in reducing all-cause mortality in people with type 2 diabetes (T2D) over a 5-year period, using real world data. We compared all cause mortality between those prescribed SGLT-2 and DPP4 inhibitors in a population resembling the EMPA-REG trial. DPP4 is selected as a comparator to SGLT-2 given it is known to be neutral with regards to cardiovascular disease (CVD). Methods Individuals were identified using Danish nationwide registries. This estimate was performed using in/exclusion criteria from EMPA-REG. We defined time zero as the first date the patient redeems either SGLT-2/DPP4. Individuals &amp;gt;=50 years of age with verified T2D and established CVD were included. CVD included myocardial infarctions, ischemic heart disease, stroke and heart failure. Individuals were only included if they had Hba1c at baseline &amp;gt; 53 mmol/mol (7.0%) The primary endpoint was all cause mortality. Survival was estimated using a Kaplan-Meier estimator in both arms. P values of less than 5% are considered significant. Results A total of 150.313 patients were identified to be on either DPP4-inhibitors or SGLT2 between 2012 and 2022. After applying EMPA-REG inclusion and exclusion criteria 15.461 patients remained (8518 on DPP4 and 6943 on SGLT2). The 5 year survival rate of SGLT2 and DPP4 was 0.780 and 0.657 respectively (p-value&amp;lt;0.0001). Conclusion In conclusion, we demonstrate, using EMPA-REG trial criteria in real-world data based on Danish nationwide registries, that five year mortality of people with T2D treated with SGLT-2 inhibitor was lower than those treated with DPP4 inhibitor.