SGLT2 Inhibitors Research Articles

Integrating artificial intelligence into a real-world clinical pathway to facilitate clinician treatment optimisation in patients with HFrEF on suboptimal medical therapy

Abstract Background Despite evidence-based pharmacological recommendations, many patients with HFrEF remain undertreated. (1) These patients remain at risk of decompensation and might benefit treatment optimisation. Many patients may also have been diagnosed with HFrEF prior to the use of sacubitril/valsartan or SGLT2 inhibitors. Identification of patients with historical HF diagnosis is time-consuming. Artificial intelligence approaches using deep learning might allow rapid identification of such patients. Aim To develop an artificial intelligence deep-learning algorithm for rapid identification of HF from electronic health records (EHRs) and to determine the potential benefit of our AI-driven algorithm for the detection of undertreated HFrEF patients in the community. Methodology In this study data was collected from EHRs of 1,200 patients who underwent transthoracic echocardiography. The records were screened to identify HF diagnosis through an AI deep-learning algorithm using a Convolutional Neural Network (CNN). Medication status of patients identified as having HFrEF was assessed to determine whether they were on optimal guideline-directed medical therapy. Accuracy of the AI algorithm was assessed by a manual clinician review in a subset of 150 patients. Eligible patients not on optimal medical therapy where no further optimisation was planned (judged to be "stable" at last visit) were invited for a clinical evaluation including NT-proBNP and Kansas City Cardiomyopathy Questionnaire (KCCQ) and offered a treatment optimization that could include either uptitration or initiation of a new medication if symptomatic. NT-proBNP and KCCQ were repeated at 12 week, pre- and post-optimization results were compared to evaluate patient outcomes. Results The deep-learning algorithm accurately identified HFrEF patients (99%) and use of RAAS inhibitors (97%) and beta-blockers (92%). 73 patients attended for initial clinical assessment (mean age 70 years, 77% male) and demonstrated a moderate level of HF-symptom burden (median NT-proBNP was 679 pg/mL, interquartile range was from 220 to 1300) and mean KCCQ overall summary score was 70, indicating a moderate level of HF symptom burden. 27 patients agreed to treatment optimisation. After 12 weeks there was a significant 22% reduction in NT-proBNP (from 1991 pg/mL (SD+/- 1796) to 1630 pg/mL (SD +/- 1588),p=0.049) and improvements in KCCQ (total symptom score 79 (+/-22) to 85 (+/-20), p=0.005; clinical summary score 78 (+/-23) to 82 (+/-20); overall summary score from 75 (+/- 24) to 80 (+/-22), both p=0.04). 23 patients (85%) and 18 patients (67%) out of 27 had an improvement in NT-proBNP and KCCQ overall summary scores respectively. Conclusion In our study we demonstrated the feasibility and potential benefits incorporating AI into a clinical workflow, allowing optimising treatment of patients with HF, with improvements in biomarkers and quality of life that could translate to long-term patient benefits.Changes in NT-proBNP after treatmentChanges in KCCQ after treatment

The effect of Trimetazidine on the left ventricular global longitudinal strain assessed by cardiac magnetic resonance in stable angina patients with previous myocardial infarction and left ventricular

Abstract Introduction Trimetazidine (TMZ) is an anti-ischemic metabolic agent that is indicated in adults as add-on therapy for the symptomatic treatment of patients with stable angina pectoris (SA). Global left ventricular (LV) systolic function is an important predictor of outcomes in patients after myocardial infarction (MI). Cardiac magnetic resonance (CMR) imaging has now evolved into a major tool for the evaluation of patients with LV dysfunction, providing precise measurements of ejection fraction (EF) and viability assessment but also now allowing assessment of global longitudinal strain (GLS) from standard cine CMR images. We hypothesized that the use of TMZ 80 mg as an anti-ischemic agent in patients with SA, history of MI, reduced EF and in the presence of viable myocardium may produce an early modification of GLS. Methods TRIM-AZ - was a non-interventional, prospective Azerbaijan study to analyze the capacity of short-term therapy with TMZ 80 mg on LV GLS evaluated by CMR in patients with previous MI. Patients with a confirmed diagnosis of heart failure (HF) with impaired LV systolic function and SA in the presence of viable myocardium were included. The treatment of all patients was optimized according to the latest ESC guidelines before entry in the study. Patients were randomized into two groups, one received TMZ 80 mg on top of guidelines directed medical therapies, and the other was the control group. A CMR as well as a transthoracic echography were performed for all patients at the inclusion visit and 8 weeks later. Results 52 patients were included in the study, 30 patients in the TMZ group and 22 in the control group,. At baseline, the mean age was 62±7 years , 63% were smokers, 60% hypertensive, 60% diabetics, 48% had a family history of MI, 12% had typical symptoms of SA while 88% had atypical form (e.g. like shortness of breath). All patients received baseline therapy with ARNI/ACE-i, SGLT2 inhibitors, beta-blockers, MRA, ASA, and statin. 8 weeks after the initiation of TMZ, there were no significant changes in LVEF assessed both by Echo and CMR (29,8%±3,2% vs 30,1%±3,5% by echo in TMZ group; 31,3%±2,7% vs 31,6%±2,7% by echo in the control group; 25,9%±3,1% vs 26,9±4,1% by CMR in TMZ group; 26,9%±2,1% vs 30,1%±2,3% by CMR in the control group), however GLS was significantly improved in TMZ group (-9,9%±1,1% to -12,7%±1,2%, p=0,00), but not in control group (-9,3%±1,3% vs -10,3%±1,4% p=0,3). No adverse event related to TMZ use was reported during the study. Conclusion These findings suggest that the use of trimetazidine in patients with stable angina , previous MI and heart failure in the presence of viable myocardium could improve the left ventricular global longitudinal strain assessed by CMR.

Takotsubo syndrome induced oxidative stress and endothelial dysfunction in left ventricle of rat model: association with NADPH oxidases/SGLT2 pro- oxidant pathway

Abstract Background Takotsubo syndrome (TTS) is characterized by apical ballooning predominantly affecting post-menopausal women following extreme physical and/or emotional stress. The phenotype of TTS is associated with akinetic apex and hyperkinetic base of the left ventricle (LV). Presently, there are no targeted therapies for TTS that can effectively reduce LV impairment. Empagliflozin (EMPA), an SGLT2 inhibitor, has shown considerable clinical benefits in managing heart failure. However, its specific effects and underlying mechanisms in treating TTS remain unclear. Purpose To explore the pathophysiology of TTS in the LV of rats, with a particular focus on the potential role of SGLT2, and to elucidate the underlying mechanisms involved. Methods Female Sprague Dawley rats (250-300 g) were allocated into four groups: a control group (n=8), a group treated with EMPA (30 mg/kg/day) (n=8), a group receiving ISO (Isoproterenol) at 100 mg/kg/day (n=18), and a group receiving both ISO and EMPA (IE) at 30 mg/kg/day (n=18). EMPA was administered orally through food two weeks prior to ISO injection. Echocardiography was conducted at 6 and 24 h, and on day 3. On day 3, rats were euthanized, and their organs were collected. Gene expression of markers was assessed using RT-qPCR, protein expression via immunofluorescence (IF) staining, and oxidative stress using dihydroethidium. Results In the ISO group, the success rate of induced Takotsubo syndrome (TTS) was 53% (10 out of 18 rats), with a mortality rate of 5%. Conversely, in the EMPA-treated group, TTS occurred in 22% of rats (4 out of 18) with no mortality observed. Significant reductions in the area of left ventricular (LV) ballooning and ejection fraction were noted in the IE group compared to the ISO group. Additionally, increased levels of reactive oxygen species (ROS) were observed in the LV of ISO rats, which were normalized by EMPA treatment in the IE rats. Furthermore, the ISO group exhibited higher protein expressions of CD68, SGLT2, and VCAM-1, which were attenuated by EMPA treatment. The mRNA expression of CYBA (p22phox) and NOX4, both representing subunits of NADPH oxidases, along with VCAM1, ICAM1, NOS2 (iNOS) and SELE (e-selectin) gene, endothelial activation marker, and TGF-β1, a fibrotic marker, showed elevated levels in the apex part of the left ventricle (LV) in the ISO group; these levels were significantly lower in the IE group. Conclusions These findings suggest that TTS is associated with oxidative stress-mediated endothelial dysfunction, inflammation, and pro-fibrotic responses. Moreover, SGLT2 inhibition appears to mitigate the pathology and progression of the syndrome. Therefore, SGLT2 inhibition emerges as an appealing and novel therapeutic approach for the treatment of TTS.

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

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

Twelve-months treatment with dapagliflozin improves endothelial glycocalyx and cardiovascular function in patients with type 1 diabetes mellitus

Abstract Background Individuals diagnosed with type 1 diabetes mellitus (T1DM) exhibit indications of vascular and endothelial dysfunction earlier in comparison to healthy individuals. Evidence shows that SGLT-2 inhibitors (SGLT-2i) have a beneficial impact on cardiovascular health in individuals with type 2 diabetes mellitus (T2DM). We investigated the effects of dapagliflozin on endothelial and cardiovascular function in patients with T1DM. Methods We recruited in total 40 patients with T1DM and pour glycemic control who were treated with insulin and received dapagliflozin (n=20) or intensification of insulin treatment (n=20) (control group). We measured at baseline and at twelve months post-treatment the: a) Carotid-femoral pulse wave velocity (PWV-Complior; ALAM Medical) b) Central systolic blood pressure (cSBP) c) Perfused boundary region (PBR) of the sublingual arterial microvessels (marker of endothelial glycocalyx thickness) and d) Left ventricular global longitudinal strain (GLS) using speckle-tracking echocardiography. Results At baseline, patients among the two groups had similar age, sex, HbA1c and markers of endothelial and cardiovascular function (p>0.05). After 12 months of treatment, patients who received dapagliflozin displayed an improvement in PBR5–25 (−16%, p<0.05), in PWV (−9.3%, p<0.05), in cSBP (−6%, p<0.05) and in GLS (+4%, P<0.05) compared to baseline. However, no statistically significant changes in PBR5–25, in PWV, in cSBP and in GLS were observed after intensification of insulin treatment (PBR5–25: +0.4%, PWV: -1%, cSBP: −2%, GLS: −1% at 4 months, P>0.05), despite a similar HbA1c reduction (Table 1). Changes of PBR after one year treatment with dapagliflozin correlated with a concomitant reduction of PWV and cSBP (P<0.05). Conclusions Twelve months treatment with dapagliflozin improves endothelial glycocalyx and cardiovascular function in patients with T1DM, independently of glycemic control.

Effects of SGLT2 inhibitors on the cardiovascular outcomes in patients with cancer: a systematic review and meta-analysis

Abstract Introduction The incidence of cardiovascular diseases in cancer survivors has gradually increased due to well-documented drug-associated cardiotoxicity and the expanding population resulting from advances in cancer treatment. Sodium-glucose cotransporter type 2 inhibitors (SGLT2i) have demonstrated efficacy in reducing cardiovascular risk in patients with type 2 diabetes mellitus, independent of glycemic control. Previous bench and animal research, along with several cohort studies, suggest potential benefits of SGLT2 inhibitors on cardiovascular outcomes in patients with cancer, with or without anthracycline therapy. This systematic review and meta-analysis aim to explore the potential of SGLT2 inhibitors as a therapeutic intervention to reduce cardiovascular risks in cancer patients, especially those undergoing chemotherapy. Methods We systematically searched Cochrane, PubMed, and Embase from inception until February 29, 2024, without language restrictions. Observational cohort studies with a follow-up period of at least 1 year were included to analyze the effects of SGLT2 inhibitors on cardiovascular outcomes in type 2 diabetes patients with cancer. Inclusion and exclusion criteria were predefined. Using random-effects models, we calculated odds ratios (OR) and 95% confidence intervals (CI). Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity and explore the impact of SGLT2 inhibitors on mitigating cardiotoxicity. Primary outcomes of interest were mortality, heart failure hospitalization, sepsis, and diabetic ketoacidosis. Results Six studies involving 2959 patients in the SGLT2i group and 29169 patients in the non-SGLT2i group were included. Type 2 diabetes patients receiving SGLT2i exhibited significantly lower odds of mortality than those without SGLT2i (OR=0.34, 95% CI=[0.26-0.46], I²=77%). Subgroup analysis revealed a similar reduction in mortality among patients on SGLT2i treated with anthracyclines (OR=0.44, 95% CI=[0.23-0.82], I²=69%). Odds ratios for heart failure hospitalization and sepsis were also significantly lower in the SGLT2i group than the non-SGLT2i group (OR=0.46, 95% CI=[0.35-0.60], I²=0%, and OR=0.28, 95% CI=[0.20-0.40], I²=0%, respectively). The risk for diabetic ketoacidosis was not increased in the SGLT2i group (OR=0.66, 95% CI=[0.20-2.17], I²=0%). Conclusion SGLT2 inhibitors demonstrate a reduction in mortality, heart failure hospitalization, and sepsis in type 2 diabetes cancer patients treated with or without anthracyclines in cohort studies. Our findings support the need for further investigation through randomized controlled trials.Forest plots of mortality with subgroupForest plots of other primary outcomes

Dapagliflozin reduces epicardial adipose tissue in patients with heart failure with reduced ejection fraction and type 2 diabetes

Abstract Introduction Epicardial adipose tissue (EAT) accumulation is associated with adverse outcome in heart failure with preserved ejection fraction, however its role in HF with reduced ejection fraction (HFrEF) is less clear. The relationship between EAT thickness and their impact on patients who have diabetes and heart failure remains unclear. SGLT2 inhibitors such as dapagliflozin improve outcomes in heart failure and diabetes, however their mechanism of benefit is not well understood. The aim of our study was to assess whether dapagliflozin reduced EAT in patients with type 2 diabetes and HFrEF. Methods We performed an analysis of individuals with type 2 diabetes and HFrEF who were randomised to receive either dapagliflozin or a placebo for 12 months as part of the REFORM trial. Participants had cardiac magnetic resonance (CMR) scans at baseline and at 12 months. Epicardial fat was measured utilizing 4-chamber cine images to quantify adipose tissue between the myocardium and the visceral layer of the pericardium. This assessment was carried out using the single end-diastolic image, with measurements conducted by evaluators blinded to the randomisation status of participants. Results 47 participants completed the stud. At baseline, not only EAT thickness and BMI level (placebo: 33, dapagliflozin 32, p=0.49) but also heart rate (74.39 bpm vs. 77.61 bpm, p=0.35), systolic blood pressure (132.75 mmHg vs. 135.00 mmHg, p=0.63), diastolic blood pressure (71.39 mmHg vs. 74.04 mmHg, p=0.33) and age (67 vs. 66, p=0.79) were comparable between the two groups. 23 randomised to placebo and 24 to dapagliflozin. Baseline EAT was similar in both groups (placebo: 11.54 cm², dapagliflozin 11.74 cm², p=0.414). After 12 months of treatment dapagliflozin caused a significant reduction in EAT compared to placebo (1.21 cm² vs. 0.09 cm², p=0.007). Conclusion Dapagliflozin significantly reduced epicardial adipose tissue compared to placebo in patients with type 2 diabetes and HFrEF. The reduction in EAT may play a role in the beneficial effects of dapagliflozin in heart failure patients.4 Ch CMRBox plot

Machine learning identifies individuals at higher risk of incident cardio-renal-metabolic diseases and cardiovascular death who have unrealised opportunities to reduce future cardiovascular risk

Abstract Background Machine learning may be able to identify individuals at risk of cardio-renal-metabolic events using routinely-collected data, and these individuals may be suitable for targeted preventative strategies.(1, 2) Purpose To train and test a machine learning algorithm to identify individuals at higher risk of incident cardio-renal-metabolic diseases and cardiovascular death, and then establish if there are opportunities to reduce their future cardiovascular risk. Methods We trained a random classifier (OPTIMISE) in UK primary care EHR data from 2 081 139 individuals aged ≥30 years (Jan 2, 1998, Nov 30, 2018), randomly divided into training (80%) and testing (20%) datasets. We calculated the cumulative incidence rate for ten cardio-renal-metabolic diseases and death. Fine and Gray’s models with competing risk of death were fit for each outcome between higher and lower predicted risk. In a multi-centre pilot interventional single arm study consenting individuals aged ≥30 years at higher predicted risk received cardio-renal-metabolic phenotyping and assessment for guideline target attainment. Results In the testing dataset (n = 416 228), individuals at higher predicted risk had higher long-term risk of heart failure (HR 12.54), aortic stenosis (HR 9.98), AF (HR 8·75), stroke/TIA (HR 8.07), CKD (HR 6.85), PVD (HR 6.62), valvular heart disease (HR 6.49), MI (HR 5.02), diabetes (HR 2.05) and COPD (HR 2.02) (Figure 1). This cohort were also at higher risk of death (HR 10.45), accounting for 74% of cardiovascular deaths (8 582 of 11 676) during 10-year follow up. Of 82 higher risk patients in the pilot study (mean age 71.6 years (SD 7.5), 50% women), the prevalence of cardio-renal-metabolic disease was high (Table 1), and there were opportunities to reduce future cardiovascular risk. Of higher risk patients with hypertension, 58.5% (31/53) of those aged <80 years had a systolic blood pressure (SBP)>140mmHg, and 54.5% (6/11) of those aged ≥80 years had a SBP >150mmHg. Of those with type 2 diabetes and co-existent ASCVD, only 23.1% (3/13) were on SGLT2 inhibitor therapy. Of higher risk patients on statin therapy, 37.0% (20/54) had LDL-cholesterol >1.8 mmol/L, and 52.0% (12/25) of patients with previous ASCVD had an LDL-cholesterol >1.4mmol/L. Furthermore, 19.5% (16/82) of the higher risk cohort had undiagnosed moderate or high risk CKD; who were infrequently prescribed a statin (41.7%; 5/12), ACE-i/ARB therapy with co-existent hypertension (61.5%. 8/13), or SGLT2 inhibitor with co-existent diabetes (83.3% (5/6)). Obesity was present in 49%, and 17% (14/82) were eligible for GLP-1 RA therapy. Conclusions The machine learning OPTIMISE algorithm can identify people at higher risk of cardio-renal-metabolic diseases and death using routinely collected data. On prospective evaluation higher risk individuals have unrecorded and undertreated cardio-renal-metabolic diseases, which are actionable targets for preventative care.Figure 1

Combination of diuretics to overcome diuretic resistance in acute heart failure: systematic review and updated network meta-analysis

Abstract Background Diuretic resistance in acute heart failure (AHF) presents a significant therapeutic challenge. While randomized clinical trials (RCTs) have compared various diuretics against furosemide, direct comparisons among these therapies are lacking. This network meta-analysis aims to fill this knowledge gap. Purpose To evaluate the efficacy and safety of various diuretic combination therapies in overcoming diuretic resistance in acute heart failure patients. Methods We conducted a systematic review and network meta-analysis of RCTs from January 2000 to December 2023. These RCTs included hospitalized AHF patients with evidence of diuretic resistance. We applied a frequentist random effects model to perform a network meta-analysis combining a total of 11 diuretic strategies compared with low-dose furosemide (reference group). Primary outcomes were urine output and weight loss at 72 hours. Secondary outcomes included cardiovascular mortality and heart failure hospitalization. The safety endpoint was the incidence of acute kidney injury across different diuretic strategies. Results Empagliflozin and high-dose furosemide showed the highest increase in urine output (SMDs: 363.94, P-score=0.64; and 306.31, P-score=0.68). For weight loss, hydrochlorothiazide led to the greatest losses (SMD: 1.33; P-score=0.20), followed by tolvaptan + furosemide low-dose (SMD: 0.85; P-score=0.43). Dapagliflozin ranked best for reducing heart failure hospitalizations (OR 0.15; P-score=0.94), and empagliflozin had the highest rank for mortality reduction (OR 0.31; P-score=0.91) but without statistical significance for mortality. Empagliflozin also showed a better safety profile (OR: 0.74; 95% CI: 0.32 to 1.71 P-score=0.87), (Figure 1 and 2). Conclusion Our findings indicate that SGLT2 inhibitors are a promising therapeutic avenue to mitigate the challenges of diuretic resistance in AHF, demonstrating potential benefits in enhancing urine output, reducing hospitalization rates, and maintaining favourable safety profile.Network and forest plots for U.O/ weightNetwork and forest plots for HHF/ AKI

A phase 2, randomized, double-blind, placebo-controlled study to assess the tolerability and pharmacodynamic effects of CRD-740, a PDE9 inhibitor, in participants with chronic heart failure

Abstract Background Natriuretic peptide (NP) receptor activation has a beneficial role in the treatment of heart failure (HF). The enzyme phosphodiesterase (PDE) 9 breaks down cGMP, the second messenger stimulated by natriuretic peptides. PDE9 inhibition may increase intracellular cGMP signaling and, potentially, have beneficial effects in HF. We examined the effects of the selective PDE9 inhibitor CRD-740 on the NP signaling pathway in HF. Purpose The objectives of this early phase 2 trial were to assess the tolerability of CRD-740 and its effects on plasma and urinary cGMP (markers of potential clinical effiacy) in patients with HFrEF, including those receving background treatment with sacubitril/valsartan. Methods Key inclusion criteria were patients with a history of HFrEF of > 6 mos, NYHA II or III, EF < 40% and NT-proBNP ≥600 pg/ml at screening (≥1000 pg/mL if in atrial fibrillation), on treatment with stable guideline-directed therapy for a minimum of 4 weeks. Patients were randomized 2:1 double-blind to CRD-740 (10mg twice daily for 2 weeks, then 25mg twice daily for 10 weeks) or placebo. Tolerability and safety were assessed. The primary pharmacodynamic endpoint was the between-group change from baseline in plasma cGMP at Week 4. Exploratory endpoints included urine cGMP levels, KCCQ and biomarkers. Results 60 patients were randomized to CRD-740 (n=40) or placebo (n=20). Baseline characteristics included age 67+13 yrs, 85% men, EF 28+7%, BMI 30+10, with 73% of patients taking sacubitril/valsartan, and 47% on SGLT2 inhibitors. The primary endpoint was positive, with placebo-corrected change in plasma cGMP significantly increased at all time points at week 4 in those treated with CRD-740 (see Table). cGMP levels were also increased on day 1 (Table) and week 2. A significant increase in urinary cGMP also was observed with CRD-740 vs placebo (Figure) in 6-hour collections at day 1 (p=0.012) and week 2 (p=0.014). In this small study, not powered for exploratory endpoints, directionally favorable placebo-corrected, baseline-adjusted changes also were seen in the KCCQ Clinical (+7.1 [95%CI, -1.6, +15.7], p=0.11) and Overall Summary Scores (+7.4 [-0.8, +15.5], p=0.075) for patients on CRD-740. No significant changes in NT-proBNP were observed between treatment groups. Adverse events (AEs) were observed in 62% and 50% of CRD-740 and placebo-treated patients, with discontinuation in 5% and 10% respectively, with no between-group difference in change in BP. There were no hypotension AEs, and no treatment-related serious adverse events. Conclusions In this early phase 2 trial, PDE9 inhibition with CRD-740 was well-tolerated and resulted in substantial elevations of plasma and urinary cGMP on top of standard care, including sacubitril/valsartan. These results support the potential of PDE9 inhibition to further activate the beneficial effects of the NP receptor-cGMP pathway incrementally to that achieved by existing HF treatments.Changes in Plasma cGMP over Time (ng/mL)Changes in Urinary cGMP over Time

Association of HbA1C with mortality and cardiovascular outcome in patients with type 2 diabetes using drugs with different hypoglycemic risk

Abstract Background Previous clinical trials showed that intensive glucose control did not reduce macrovascular events and mortality. It was speculated that severe hypoglycaemia contributed to these adverse outcomes. More contemporary clinical trials using newer anti-diabetic agents with less hypoglycaemic potential showed a linear relationship between major adverse cardiovascular events (MACE) and HbA1c reduction according to a meta-regression analysis. Purpose The aim of this study was to examine the association between clinical outcomes and HbA1c under different treatment backgrounds in the real-world setting. We hypothesised that when using drugs with minimal hypoglycaemic risk, lower HbA1c would be associated with better outcomes. Methods This was a retrospective population-based cohort study using a multi-centre electronic medical record database. Eligible patients were those diagnosed with type 2 diabetes between 2009 and 2020 who received non-insulin antidiabetic drugs. Patients were stratified into two groups based on the drugs received: drugs with high hypoglycaemic risk (sulphonylurea, meglitinide) and drugs with low hypoglycaemic risk (thiazolidinediones, acarbose, DPP4 inhibitors, GLP1 agonists, SGLT-2 inhibitors). Patients were excluded if they had received these drugs for less than 180 days or had received both high and low hypoglycaemic risk oral drugs simultaneously. HbA1c levels were assessed from the index date to the date of the interested outcome or the end of the study period (31 December 2021), whichever came first. The relationship between HbA1c and clinical outcomes was examined using a Cox proportional hazards model. The outcomes of interest included all-cause mortality and MACE. Results The study population consisted of 6,923 patients, including 3,639 high hypoglycaemic risk drug users and 3,284 low hypoglycaemic risk drug users. Patients with lower HbA1c levels during the follow-up period were older and frailer. After adjusting for baseline covariates, the association between the risk of death and HbA1c presented a U-shaped pattern, and this U-shaped association was similar in the two treatment cohorts (Table 1). On the other hand, the association between the risk of MACE and HbA1c presented a J-shaped pattern. In the high hypoglycaemic risk drug cohort, patients with the highest HbA1c levels (mean HbA1c 9.6%) were associated with a higher risk of MACE compared to the group with a mean HbA1c of 7.2% (hazard ratio [HR] 4.16, 95% confidence interval [CI] 2.07-8.37); lower HbA1c levels were not associated with a lower risk of MACE (Table 2). In contrast, in the low hypoglycaemic risk drug cohort, lower HbA1c levels were associated with a higher risk of MACE (HR 3.82, 95% CI 1.29-11.28). Conclusion Lower HbA1c levels were not associated with a lower risk of all-cause mortality and MACE. Furthermore, this phenomenon was independent of the hypoglycaemic risk of anti-diabetic drugs.

Efficacy of sotagliflozin by diabetes duration: a secondary analysis of SCORED

Abstract Background Sotagliflozin is a sodium-glucose cotransporter (SGLT) 1 and SGLT2 inhibitor. SCORED randomized patients with type 2 diabetes (DM) and high cardiovascular (CV) risk to sotagliflozin or placebo. Purpose We evaluated if diabetes duration affects HF and CV outcomes when comparing sotagliflozin with placebo in SCORED, as diabetes duration can modify CV risk. Methods SCORED enrolled patients with DM (hemoglobin A1c ≥7%), chronic kidney disease (glomerular filtration rate of 25-60 mL/minute per 1.73 m2), and CV risk factors. Patients were randomized to sotagliflozin compared with placebo. Patients in SCORED were stratified by diabetes duration, into categories of <10 years, 10-19 years, or ≥20 years. The primary endpoint was total CV death, hospitalization for HF, or urgent visit for HF. Secondary endpoints were total hospitalization for HF or urgent visit for HF, as well as total CV death, nonfatal myocardial infarction, and nonfatal stroke (MACE). Outcomes were assessed using marginal proportional hazard models stratified according to HF criteria and geographic region where non-CV death was a competing terminal event. Subgroup analyses were assessed with natural cubic splines of interaction between treatment and continuous diabetes duration. Results In SCORED, 10,579 (99.9%) of 10,584 patients had complete data on diabetes duration, with 2412 (22.8%), 4424 (41.8%), 3743 (25.9%) having diabetes duration of <10, 10-19, and ≥20 years respectively. Median (Q1, Q3) diabetes duration was 16.4 years (10.4, 22.4 years), while mean hemoglobin A1c was 8.6%, 8.7%, and 8.7% respectively by diabetes duration. The rate of the primary endpoint was lower in the sotagliflozin group (5.6 events per 100 patient-years [p-y]) compared with the placebo group (7.5 events per 100 p-y) (HR: 0.74; 95% CI: 0.63, 0.88). Event rates among diabetes duration subgroups indicated that rates in both the placebo group and relative treatment benefit increased with increasing diabetes duration, with 5.6 vs 5.8 events per 100 p-y, 6.1 vs 7.4 events per 100 p-y, and 4.6 vs 8.5 events per 100 p-y for diabetes duration <10, 10-19, and ≥20 years respectively. Spline analysis indicated increasing treatment benefit with increasing duration when modeled continuously (Figure Panel A; PSpline=0.02). Similar findings were observed for the secondary HF outcome of hospitalization for HF or urgent visit for HF, with increased treatment benefit with duration (Figure Panel B; PSpline=0.10). Total MACE was lower in the sotagliflozin group (4.8 events per 100 patient-years) than in the placebo group (6.3 events per 100 patient-years) (HR: 0.77; 95% CI: 0.65, 0.91), without significant difference in relative treatment benefit by duration (Figure Panel C; PSpline=0.30). Conclusions Sotagliflozin improved HF and MACE outcomes in patients with high CV risk, with increasing treatment benefit for HF outcomes among patients with longer diabetes duration.

SGLT2 Inhibition: A New Glimmer of Hope to Slow Chronic Kidney Disease Progression in Children?

SGLT2 Inhibition: A New Glimmer of Hope to Slow Chronic Kidney Disease Progression in Children?

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

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

Effects of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors on Health-Related Quality of Life and Exercise Capacity in Heart Failure Patients With a Preserved Ejection Fraction: A Scoping Review

Effects of Sodium-Glucose Cotransporter-2 (SGLT-2) Inhibitors on Health-Related Quality of Life and Exercise Capacity in Heart Failure Patients With a Preserved Ejection Fraction: A Scoping Review

Determinants of changes in peak oxygen consumption in patients with new onset heart failure

Abstract Background Patients with heart failure (HF) with reduced ejection fraction (HFrEF) have a high risk of mortality. Cardio-Pulmonary Exercise Test (CPET) assesses peak oxygen consumption (pVO2) which is considered a key predictor of mortality and morbidity in patients with HFrEF. Factors responsible for the changes in pVO2 could consequently be of interest, as optimizing these factors may improve prognosis and overall quality of life in patients with HFrEF. Purpose To investigate factors contributing to changes in pVO2 within a contemporary cohort of new-onset patients with HFrEF. Methods From December 2022 to September 2023, patients with new-onset HFrEF (European Society of Cardiology (ESC) criteria) were included from a HF outpatient clinic, who after referral to the clinic underwent 12 weeks of HF management according to ESC guidelines. This included physical training and optimization of pharmacological management of HFrEF. Baseline characteristics, CPET, medication and echocardiography were collected at referral and after 12 weeks. Changes in pVO2 were investigated according to baseline characteristics, changes in medication, and changes in echocardiographic parameters in both uni- and multivariable linear regression models. Significant independent variables were identified using stepwise selection (p<0.1), adjusted for age and sex. A p-value of 0.05 was considered significant. Results We included 48 patients with new-onset HFrEF with a median age of 73 (interquartile range (IQR): 60-77) years, 10 (20.8%) women, a baseline median left ventricular ejection fraction (LVEF) of 30% (IQR: 25-35), and a baseline median pVO2 of 17.3 ml/min/kg (IQR: 14.1-21.9). After 12 weeks, pVO2 improved with a mean of +2.18 ml/min/kg (95% confidence interval (CI) 1.25 to 3.10, p<0.01) and LVEF improved with a mean of +11.7% (95% CI 7.9 to 15.6, p<0.01). In univariable analyses increasing age were negatively associated with pVO2 changes (p=0.04) and increasing minute ventilation (MV) and initiation of sodium-glucose cotransporter (SGLT2) inhibitors were all positively associated with pVO2 changes (p<0.01 and p=0.03, respectively). Other clinical variables included in the analysis were not significantly associated with a change in pVO2. In the multivariable analysis, body mass index emerged as an independent variable negatively associated with pVO2 changes, and MV and initiation of SGLT2 inhibitors remained significantly positively associated with pVO2 changes. Conclusion Optimal pharmacological management and physical training in patients with new-onset HFrEF, induce a significant recovery of cardiorespiratory performance and ejection fraction. Furthermore, our results suggest that the initiation of SGLT2 inhibitors in patients with new-onset HFrEF appears to improve their pVO2 already after 12 weeks of optimal HF management.Table 1:BaselineTable 2:Associations

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.

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<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<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<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.

Effects of dapagliflozin on body composition and its relation to hemodynamics in heart failure with preserved ejection fraction: the CAMEO-DAPA randomized clinical trial

Abstract Background Excess fat, particularly visceral fat, plays an important role in the development of heart failure with preserved ejection fraction (HFpEF). Sodium glucose cotransporter-2 inhibitors improve hemodynamics, reduce symptom severity, and decrease risk of hospitalization, but their impact on body composition, as well as potential relationships between changes in body composition and hemodynamic effects, are unknown in HFpEF. Purpose Evaluate the effect of dapagliflozin on body and blood composition and examined the potential correlation of such changes on cardiac hemodynamics. Methods The CAMEO-DAPA trial, a single-center, double-blind, randomized, placebo-controlled study, showed that 24 weeks of dapagliflozin reduced resting and exercise pulmonary capillary wedge pressures (PCWP) in patients with HFpEF. This prespecified secondary analysis reports the effects of dapagliflozin on body composition using dual energy x-ray absorptiometry (DEXA), blood composition (radiolabeled iodinated albumin), and cardiac hemodynamics using high-fidelity micromanometers. Analysis was performed based on the intention-to-treat. Relative change was calculated by dividing the absolute change on the baseline value. Results Overall, 37 patients (67 years, 65% women, 70% with obesity, 27% overweight) completed the trial. As compared with baseline, dapagliflozin decreased total body fat compared with placebo [mean (SD) absolute change: -2.29 (2.94) kg vs -0.32 (1.84) in placebo, p=0.03; relative change: -4.6% (5.4) vs -0.8% (4.3), p=0.02], Figure 1. This was primarily due to greater loss of upper body trunk fat [absolute change: -1.53 (1.70) kg vs +0.31 (0.99) in placebo, p<.001; relative change: -5.2% (5.6) vs +1.1% (4.1), p<.001], Figure 1. Reductions in trunk fat were correlated with decreases in PCWP (r=0.41, p=0.03), Figure 2. Total body fat-free mass (FFM) tended to decrease in the dapagliflozin group [absolute change: -0.63 (1.85) kg vs +0.34 (1.76), p=0.12]; reductions in leg, android, and gynoid FFM were all greater than placebo (p<0.05). Dapagliflozin reduced plasma volume [absolute change: -170 (343) ml vs +112 (346), p=0.02] compared with placebo, and the decrease in plasma volume was correlated with the reduction in FFM (r=0.47, p=0.006), Figure 2. Treatment with dapagliflozin had no effect on resting metabolic rate but was associated with modest reduction in bone mineral content [-16 (47) g vs +26 (61), p=0.03]. Conclusions In patients with HFpEF, dapagliflozin decreases body fat, particularly trunk fat, suggesting greater effect on visceral adipose, which is correlated with favorable hemodynamic effects. Dapagliflozin also tends to reduce FFM, which may relate to reduction in total body water with or without reduction is muscle mass, in tandem with modest decreases in bone mineral content.Figure 1:Relative change in fat massFigure 2

Canagliflozin reduces oral loop diuretic intensification in patients with type 2 diabetes: a participant level pooled analysis of CREDENCE and CANVAS

Abstract Background Patients with type 2 diabetes often have coexistent heart failure or chronic kidney disease (CKD) that require treatment with loop diuretics; however, the prognostic implications of oral loop diuretic intensification are not well characterized. The sodium glucose cotransporter-2 inhibitor canagliflozin reduces the risk of hospitalization for heart failure or cardiovascular death and CKD progression among patients with type 2 diabetes at high cardiovascular risk or with concomitant CKD. Purpose To assess the prognostic implications of oral loop diuretic intensification and the treatment effects of canagliflozin versus placebo on loop diuretic use in high-risk patients with type 2 diabetes. Methods This was a post-hoc participant-level pooled analysis of the CANVAS Program and CREDENCE trial which enrolled patients with type 2 diabetes at high cardiovascular risk or with CKD. Oral loop diuretic intensification was defined as a composite of new loop diuretic initiation (among patients not receiving loop diuretics at baseline) or loop diuretic dose increase (among patients receiving loop diuretics at baseline). We assessed the association between the requirement for loop diuretic intensification and the incidence of subsequent all-cause death. The effect of canagliflozin versus placebo on the composite of loop diuretic intensification as well as its components were evaluated. We further examined the effect of canagliflozin on an expanded post hoc composite of cardiovascular death, hospitalization for heart failure or loop diuretic intensification. Results 2,263 (15.6%) of 14,543 patients were treated with loop diuretics at baseline. Over a median follow-up of 2.2 years, 1,264 patients (9.4%) required oral loop diuretic intensification, of which 981 (77.6%) patients required initiation of oral loop diuretics and 283 (22.4%) required oral loop diuretic dose increase. Patients requiring oral loop diuretic intensification experienced rates of subsequent mortality that were 3.5-fold higher (5.9[5.4-6.5] per 100 patient-years) than those not requiring oral loop diuretic intensification (1.7[1.6-1.9] per 100 patient-years). Treatment with canagliflozin reduced the need for oral loop diuretic intensification by 41% (HR 0.59; 95%CI: 0.53-0.66) including both new diuretic initiation (HR 0.65; 95%CI: 0.57-0.74) and diuretic dose increase (HR 0.42; 95%CI: 0.33-0.54); Figure 1. Treatment with canagliflozin similarly reduced an expanded composite of worsening heart failure inclusive of cardiovascular death, heart failure hospitalization or diuretic intensification (HR 0.64; 95%CI: 0.58-0.70). Conclusion Among high-risk patients with T2D, new oral loop diuretic intensification was frequent and associated with an increased risk of subsequent mortality. Treatment with canagliflozin significantly reduced the need for loop diuretic intensification.