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Background: Sodium-Glucose Cotransporter-2 inhibitors (SGLT2i) represent a deep revolution of the therapeutic approach to heart failure (HF), preventing its insurgence but also improving the management of the disease and slowing its natural progression. To date, few studies have explored the effectiveness of SGLT2i and, in particular, Dapagliflozin in a real-world population. Therefore, in this observational prospective study, we evaluated Dapagliflozin's effectiveness in a real-world HF population categorized in the different hemodynamic profiles., Methods: From January 2022 to June 2023, we enrolled 240 patients with chronic HF and reduced ejection fraction (HFrEF) on optimal medical therapy, according to 2021 ESC guidelines, that added treatment with Dapagliflozin from the HF Clinics of 6 Italian University Hospitals. Clinical, biochemical, and echocardiographic parameters were collected before and after 6 months of Dapagliflozin introduction. Moreover, the HFrEF population was classified according to hemodynamic profiles (A: SV ≥ 35 ml/m 2 ; E/e' < 15; B: SV ≥ 35 ml/m 2 ; E/e' ≥ 15; C: SV < 35 ml/m 2 ; E/e' < 15; D: SV < 35 ml/m 2 ; E/e' ≥ 15). Then, we compared the Dapagliflozin population with two retrospective HF cohorts, hereinafter referred to as Guide Line 2012 (GL 2012) group and Guide Line 2016 (GL 2016) group, in accordance with the HF ESC guidelines in force at the time of patients enrolment. Precisely, we evaluated the changes to baseline in clinical, functional, biochemical, and echocardiographic parameters and compared them to the GL 2012 and GL 2016 groups., Results: Dapagliflozin population (67.18 ± 11.11 years) showed a significant improvement in the echocardiographic and functional parameters (left ventricular ejection fraction [LVEF], LV end-diastolic volume [LVEDV], LVEDV index, stroke volume index [SVi], left atrium volume index [LAVi], filling pressure [E/e' ratio], tricuspid annular plane systolic excursion [TAPSE], tricuspid annular S' velocity [RVs'], fractional area change [FAC], inferior vena cava [IVC diameter], pulmonary artery systolic pressure [sPAP], NYHA class, and quality of life) compared to baseline. In particular, TAPSE and right ventricle diameter (RVD1) ameliorate in congestive profiles (B and D); accordingly, the furosemide dose significantly decreased in these profiles. Comparing the three populations, the analysis of echocardiographic parameters (baseline vs follow-up) highlighted a significant decrease of sPAP in the Dapagliflozin population (p < 0.05), while no changes were recorded in the GL 2012 and GL 2016 population. Moreover, at the baseline evaluation, the GL 2012 and 2016 groups needed a higher significant dose of furosemide compared to Dapagliflozin group. Finally, Dapagliflozin patients had significantly fewer rehospitalizations (1.25%) compared with the other two groups (GL 2012 18.89%, p 0.0097; GL 2016 15.32%, p 0.0497)., Conclusions: We demonstrate that Dapagliflozin is rapidly effective in an HFrEF real-world population; furthermore, the more significant effect is recorded in HFrEF patients with a congestive profile (B and D), supporting the introduction of Dapagliflozin in patients with a congestive profile and a worse prognosis. In conclusion, our data suggest evaluating the patient's hemodynamic state beyond LVEF in HFrEF., Competing Interests: Declarations. Ethics approval and consent to participate: Informed consent was obtained from all participants. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors exert a distinctive pattern of direct biological effects on the heart and kidney under experimental conditions, but the meaningfulness of these signatures for patients with heart failure has not been fully defined., Objectives: We performed the first mechanistic validation study of large-scale proteomics in a double-blind randomized trial of any treatment in patients with heart failure., Methods: In a discovery cohort from the EMPEROR (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure and Reduced Ejection Fraction) program, we studied the effect of randomized treatment with placebo or empagliflozin on 1,283 circulating proteins in 1,134 patients with heart failure with a reduced or preserved ejection fraction. In a validation cohort, we expanded the number to 2,155 assessed proteins, which were measured in 1,120 EMPEROR participants who had not been studied previously., Results: In the validation cohort, 25 proteins were the most differentially enriched by empagliflozin (ie, ≥15% between-group difference and false discovery rate <1% at 12 weeks with known effects on the heart or kidney): 1) 13 proteins promote autophagy and other cellular quality-control functions (IGFBP1, OTUB1, DNAJB1, DNAJC9, RBP2, IST1, HSPA8, H-FABP, FABP6, ATPIFI, TfR1, EPO, IGBP1); 2) 12 proteins enhance mitochondrial health and ATP production (UMtCK, TBCA, L-FABP, H-FABP, FABP5, FABP6, RBP2, IST1, HSPA8, ATPIFI, TfR1, EPO); 3) 7 proteins augment cellular iron mobilization or erythropoiesis (TfR1, EPO, IGBP1, ERMAP, UROD, ATPIF1, SNCA); 4) 3 proteins influence renal tubular sodium handling; and 5) 9 proteins have restorative effects in the heart or kidneys, with many proteins exerting effects in >1 domain. These biological signatures replicated those observed in our discovery cohort. When the threshold for a meaningful between-group difference was lowered to ≥10%, there were 58 additional differentially enriched proteins with actions on the heart and kidney, but the biological signatures remained the same., Conclusions: The replication of mechanistic signatures across discovery and validation cohorts closely aligns with the experimental effects of SGLT2 inhibitors. Thus, the actions of SGLT2 inhibitors-to promote autophagy, restore mitochondrial health and production of ATP, promote iron mobilization and erythropoiesis, influence renal tubular ion reabsorption, and normalize cardiac and renal structure and function-are likely to be relevant to patients with heart failure. (EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction [EMPEROR-Preserved], NCT03057951; EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction [EMPEROR-Reduced], NCT03057977)., Competing Interests: Funding Support and Author Disclosures The authors met criteria for authorship as described by the International Committee of Medical Journal Editors (ICMJE). No author received payment related to the development of the manuscript. Boehringer Ingelheim was given the opportunity to review the manuscript for medical and scientific accuracy as well as intellectual property considerations. The study was supported and funded by the Boehringer Ingelheim & Eli Lilly and Company Diabetes Alliance. To ensure independent interpretation of clinical trial results and enable authors to fulfill their role and obligations under the ICMJE criteria, Boehringer Ingelheim grants all external authors access to relevant clinical study data. In adherence with the Boehringer Ingelheim Policy on Transparency and Publication of Clinical Study Data, scientific and medical researchers can request access to clinical study data, typically 1 year after the approval has been granted by major regulatory authorities or after termination of the development program. Researchers should use the https://vivli.org/ link to request access to study data and visit https://www.mystudywindow.com/msw/datasharing for further information. Dr Packer has received consulting fees from 89bio, Abbvie, Actavis, Altimmune, Ardelyx, ARMGO Pharma, Attralus, Amgen, Alnylam, AstraZeneca, Biopeutics, Boehringer Ingelheim, Caladrius, Casana, Cytokinetics, Eli Lilly & Company, Imara, Moderna, Medtronic, Novartis, Pharmacosmos, Reata, Regeneron, and Salamandra. Dr Ferreira has served as consultant for Boheringer Ingelheim and AstraZeneca. Dr Butler has received consulting fees from Abbott, American Regent, Amgen, Applied Therapeutic, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimension, Cardior, CVRx, Cytokinetics, Edwards, Element Science, Innolife, Impulse Dynamics, Imbria, Inventiva, Lexicon, Lilly, LivaNova, Janssen, Medtronic, Merck, Occlutech, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Pharmain, Roche, Sequana, SQ Innovation, and Vifor. Dr Filippatos has received consulting fees from Bayer, Boehringer Ingelheim, and Servier; has received lecture fees from Novartis; has received trial committee membership fees from Impulse Dynamics, Vifor, and Medtronic; has served on trial committee for Cardior; and has received consulting fees from Novo Nordisk. Dr Maldonado has received consulting fees from Boehringer Ingelheim Pharma GmbH & Co KG. Dr Saadati has served as freelance statistician for Boehringer. Dr Sattar has served in advisory positions for Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Novartis, Novo Nordisk, Pfizer, and Roche Diagnostics; has received consulting fees from Abbott Laboratories, AbbVie, Amgen, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Hanmi Pharmaceuticals, Janssen, Menarini-Ricerche, Novo Nordisk, Pfizer, and Sanofi; has received speaker fees from Abbott Laboratories, AbbVie, AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Novo Nordisk, and Sanofi; and has received research grants from AstraZeneca, Boehringer Ingelheim, Novartis, and Roche Diagnostics. Dr Anker has received grants and personal fees from Vifor and Abbott Laboratories; has received personal fees for consultancies, trial committee work and lectures from Actimed, AstraZeneca, Bayer, Bioventrix, Boehringer Ingelheim, Brahms, Cardiac Dimensions, Cardior, Cordio, CVRx, Cytokinetics, Edwards, Farraday Pharmaceuticals, GSK, HeartKinetics, Impulse Dynamics, Medtronic, Novartis, Novo Nordisk, Occlutech, Pfizer, Regeneron, Relaxera, Repairon, Scirent, Sensible Medical, Servier, Vectorious, and V-Wave; and is named co-inventor of 2 patent applications regarding MR-proANP (DE 102007010834 & DE 102007022367), but he does not benefit personally from the related issued patents. Drs Gonzalez Maldonado, Panova-Noeva, Prochaska, Saadati, and Sumin are employees of Boehringer Ingelheim. Dr Zannad has served on the Steering Committee or Data Safety Monitoring Board for or served as a consultant to 89bio, Applied Therapeutics, Bayer, Betagenon, Biopeutics, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Cardior, Cereno, Cellprothera, CEVA, Merck, Northsea, Novartis, NovoNordisk, Otsuka, Owkin, Salubris, and Servier; has equity in Cardior, G3Pharmaceutical, Cereno Pharmaceutical, and CVCT; and has lectured for Bayer, Boehringer Ingelheim, CVRx, CEVA, Merck, and Novartis. All other authors have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Today, sodium glucose co-transporter 2 (SGLT2) inhibitors are more than diabetes drugs. They are also indicated in chronic heart failure (HF) treatment in both diabetic and non-diabetic patients, independently of the ejection fraction. Multiple mechanisms have been suggested behind the cardioprotective effects of SGLT2 inhibitors. However, the underlying mechanisms still remain largely unexplored. Here, we used a zebrafish embryo model to search for new potential players whereby SGLT2 inhibitors attenuate HF., Methods: HF in zebrafish embryos was caused exposing them to chemically induced hypoxia. As a SGLT2 inhibitor, we used empagliflozin. Its effect on hypoxia-induced HF of the embryos was evaluated using video microscopy and calculation of fractional shortening (FS) of embryos´ hearts. RT-qPCR of brain natriuretic peptide (bnp) expression was also used to examine empagliflozin´s effect on HF. Transcriptome analysis of total RNA of the embryos was performed to search for new potential mechanisms contributing to the beneficial effect of empagliflozin on HF., Results: Empagliflozin significantly attenuated hypoxia-induced HF of zebrafish embryos as shown with improved FS of the hearts and decreased bnp expression. Transcriptome analysis revealed that the improvement of HF in response to empagliflozin was accompanied with decreased matrix metalloproteinase 13a (mmp13a) expression. Treatment of hypoxia-induced embryos with MMP13 inhibitor ameliorated the impaired heart function accordingly to the effect of empagliflozin. MMP13 inhibitor was not toxic to the embryos., Conclusions: Our study shows that empagliflozin´s favorable effect on attenuating HF is mediated via MMP13. MMP13 provides a novel option when developing new therapeutics for HF treatment., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hannu Jarvelainen reports financial support was provided by Satasairaala Central Hospital, The Wellbeing Services County of Satakunta Hannu Jarvelainen reports financial support was provided by Finnish Foundation for Cardiovascular Diseases. Hannu Jarvelainen reports financial support was provided by Turku University Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Aims: Sodium-glucose cotransporter inhibitors (SGLT2-i) improve outcomes in patients with heart failure (HF) and reduced ejection fraction (HFrEF). However, evidence in patients with advanced HF is lacking. We aimed to determine the effect of SGLT2-i in advanced HFrEF compared to their effect on a non-advanced population., Methods: Consecutive HFrEF outpatients who started SGLT2-i were observed for 6-months. Patients were categorized as having advanced or non-advanced HFrEF. The primary outcome was the trend of NTproBNP in the two groups. Secondary outcomes included changes in New York Heart Association (NYHA) class, glomerular filtration rate (GFR), and ejection fraction (LVEF). The association between advanced HF diagnosis and including N-terminal pro-brain natriuretic peptide (NTproBNP) reduction was tested using multivariate analysis., Results: Overall, 105 patients (45 advanced, 60 non-advanced) were included. Mean age was 56 ± 10 years, 22 % were female, and 35 % had ischemic heart disease. Median NTproBNP at baseline for advanced and non-advanced patients was 1672pg/ml (IQR 520-3320) vs. 481 pg/ml (IQR 173-917), respectively (p < 0.001). At follow-up, only non-advanced patients reduced their NTproBNP (-32 % (95 % CI -51 to -3), p < 0.001), while advanced patients had an increase in NTproBNP. LVEF and NYHA class improved only in non-advanced patients. GFR was stable in both subgroups. At multivariate analysis a diagnosis of advanced HF was independently associated with a reduced probability of NTproBNP reduction (OR 0.041 (95 % CI 0.002-0.752), p = 0.031). Only one patient discontinued the drug due to side effects., Conclusion: In advanced HFrEF, SGLT2-i do not impact on NTproBNP, LVEF or NYHA class but are well tolerated., Competing Interests: Declaration of competing interest The authors have not any conflict of interest to declare, (Copyright © 2024 Elsevier Inc. All rights reserved.)

Sodium glucose cotransporter 2 inhibitors (SGLT2i) constitute the only medication class that consistently prevents or attenuates human heart failure (HF) independent of ejection fraction. We have suggested earlier that the protective mechanisms of the SGLT2i Empagliflozin (EMPA) are mediated through reductions in the sodium hydrogen exchanger 1 (NHE1)-nitric oxide (NO) pathway, independent of SGLT2. Here, we examined the role of SGLT2, NHE1 and NO in a murine TAC/DOCA model of HF. SGLT2 knockout mice only showed attenuated systolic dysfunction without having an effect on other signs of HF. EMPA protected against systolic and diastolic dysfunction, hypertrophy, fibrosis, increased Nppa/Nppb mRNA expression and lung/liver edema. In addition, EMPA prevented increases in oxidative stress, sodium calcium exchanger expression and calcium/calmodulin-dependent protein kinase II activation to an equal degree in WT and SGLT2 KO animals. In particular, while NHE1 activity was increased in isolated cardiomyocytes from untreated HF, EMPA treatment prevented this. Since SGLT2 is not required for the protective effects of EMPA, the pathway between NHE1 and NO was further explored in SGLT2 KO animals. In vivo treatment with the specific NHE1-inhibitor Cariporide mimicked the protection by EMPA, without additional protection by EMPA. On the other hand, in vivo inhibition of NOS with L-NAME deteriorated HF and prevented protection by EMPA. In conclusion, the data support that the beneficial effects of EMPA are mediated through the NHE1-NO pathway in TAC/DOCA-induced heart failure and not through SGLT2 inhibition., (© 2024. The Author(s).)

Background: Sodium-glucose cotransporter-2 inhibitors (SGLT2is) are novel agents for heart failure (HF) and are now recommended in guidelines. Understanding general physicians' perspectives can help to optimise utilisation of this new medication., Aim: To understand the clinical concerns and barriers from general physicians about prescribing SGLT2is in a general medicine cohort., Methods: A questionnaire exploring clinicians' experience, comfort level and barriers to prescribing SGLT2is in patients with HF, incorporating two clinical scenarios, was disseminated to Internal Medicine Society of Australia and New Zealand members over a 2-month period., Results: Ninety-eight participants responded to the questionnaire (10.8% response rate). Most respondents (66.3%) were senior medical staff. Most participants worked in metropolitan settings (64.3%) and in public hospital settings (83.7%). For HF with reduced ejection fraction, 23.5% of participants reported prescribing SGLT2is frequently (defined as prescribing SGLT2is frequently over 75% of occasions). For HF with preserved ejection fraction, 57.1% of participants reported prescribing SGLT2is less than 25% of the time. Almost half of the participants (44%) expressed a high level of familiarity with therapeutic knowledge of SGLT2is, while 47% indicated high familiarity with potential side effects. Patient complexity, cost of medications and discontinuity of care were identified as important barriers. Euglycemic diabetic ketoacidosis was the side effect that caused the most hesitancy to prescribe SGLT2is in 48% of the respondents., Conclusion: General physicians in Australia and Aotearoa New Zealand are familiar with the therapeutic knowledge and side effects of SGLT2is. Patient complexity, medication cost and discontinuity of care were significant barriers to the use of SGLT2is for HF among general physicians., (© 2024 The Author(s). Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Aims: People with type 2 diabetes (T2D) face high risks of heart failure (HF) hospitalizations that are often recurrent, especially as kidney function declines. We examined the effects of canagliflozin on total HF events by baseline kidney function in patients with T2D at high cardiovascular risk and/or with chronic kidney disease., Methods and Results: Leveraging pooled participant-level data from the CANVAS programme (n = 10 142) and CREDENCE trial (n = 4401), first and total HF hospitalizations were examined. Cox proportional hazards models were built for the time to first HF hospitalization, and proportional means models based on cumulative mean functions were used for recurrent HF hospitalizations. Treatment effects were evaluated overall as well as within baseline estimated glomerular filtration rate (eGFR) strata (<45, 45-60, and >60 ml/min/1.73 m 2 ). HF hospitalizations were independently and blindly adjudicated. Among 14 540 participants with available baseline eGFR values, 672 HF hospitalizations occurred over a median follow-up of 2.5 years. Among participants who experienced a HF hospitalization, 357 had a single event (201 in placebo-treated patients and 156 in canagliflozin-treated patients), 77 had 2 events, and 39 had >2 events. Canagliflozin reduced risk of first HF hospitalization (hazard ratio 0.58, 95% confidence interval [CI] 0.48-0.70) consistently across baseline eGFR strata (p interaction  = 0.84). Canagliflozin reduced total HF hospitalizations overall (mean event ratio 0.63, 95% CI 0.54-0.73) and across eGFR subgroups (p interaction  = 0.51). Canagliflozin also reduced cardiovascular death and total HF hospitalizations (mean event ratio 0.72, 95% CI 0.65-0.80) and across eGFR subgroups (p interaction  = 0.82). The absolute risk reductions were numerically larger, and numbers needed to treat were smaller when evaluating total events versus first events alone. These observed HF benefits were highly consistent across the range of eGFR, with larger absolute benefits in participants who had worse kidney function at baseline., Conclusions: In individuals with T2D at high cardiovascular risk and/or with chronic kidney disease, canagliflozin reduced the total burden of HF hospitalizations, with consistent benefits observed across the kidney function spectrum., Clinical Trial Registration: ClinicalTrials.gov Identifier: CANVAS (NCT01032629), CANVAS-R (NCT01989754), CREDENCE (NCT02065791)., (© 2024 European Society of Cardiology.)

Background: Heart failure with preserved ejection fraction (HFpEF) is common in type 2 diabetes mellitus (T2D), leading to high morbidity and mortality. Managing HFpEF in diabetic patients is challenging with limited treatments. Sodium-glucose co-transporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1-RA) have shown potential cardiovascular benefits. This meta-analysis compares the effects of GLP1-RA and SGLT2 inhibitors on HFpEF in T2D patients., Methods: We conducted a meta-analysis of randomized controlled trials (RCTs) and observational studies evaluating GLP1-RA and SGLT2 inhibitors' impact on HFpEF in T2D patients. Databases searched included PubMed, MEDLINE, and Cochrane Library up to July 2024. Primary outcomes were changes in left ventricular ejection fraction (LVEF), myocardial fibrosis (extracellular volume fraction, ECV), and functional capacity (6-minute walk test, 6MWT). Secondary outcomes included HbA1c, body weight, and systolic blood pressure (SBP).  RESULTS: Twelve studies with 3,428 patients (GLP1-RA: 1,654; SGLT2 inhibitors: 1,774) were included. Both GLP1-RA and SGLT2 inhibitors significantly improved LVEF compared to placebo (GLP1-RA: mean difference [MD] 2.8%, 95% confidence interval [CI] 1.5 to 4.1, p < 0.001; SGLT2 inhibitors: MD 3.2%, 95% CI 2.0 to 4.4, p < 0.001). SGLT2 inhibitors significantly reduced myocardial fibrosis (MD -3.5%, 95% CI -4.2 to -2.8, p < 0.001) more than GLP1-RA (MD -2.3%, 95% CI -3.0 to -1.6, p < 0.001). Functional capacity improved significantly with both treatments (GLP1-RA: MD 45 m, 95% CI 30 to 60, p < 0.001; SGLT2 inhibitors: MD 50 m, 95% CI 35 to 65, p < 0.001). Secondary outcomes showed reductions in HbA1c (GLP1-RA: MD -1.1%, 95% CI -1.4 to -0.8, p < 0.001; SGLT2 inhibitors: MD -1.0%, 95% CI -1.3 to -0.7, p < 0.001) and body weight (GLP1-RA: MD -2.5 kg, 95% CI -3.1 to -1.9, p < 0.001; SGLT2 inhibitors: MD -2.0 kg, 95% CI -2.6 to -1.4, p < 0.001). Both treatments significantly lowered SBP (GLP1-RA: MD -5.2 mmHg, 95% CI -6.5 to -3.9, p < 0.001; SGLT2 inhibitors: MD -4.8 mmHg, 95% CI -6.0 to -3.6, p < 0.001)., Conclusions: GLP1-RA and SGLT2 inhibitors significantly benefit HFpEF management in T2D patients. SGLT2 inhibitors reduce myocardial fibrosis more effectively, while both improve LVEF, functional capacity, and metabolic parameters. These therapies should be integral to HFpEF management in diabetic patients. Further research is needed on long-term outcomes and potential combined therapy effects., (© 2024. The Author(s).)

Purpose: Multiple randomized controlled trials have presented SGLT2 inhibitors (SGLT2i) as novel pharmacological therapy for patients with heart failure, resulting in reductions in hospitalization for heart failure and mortality. Given the absence of SGLT2 receptors in the heart, mechanisms of direct cardioprotective effects of SGLT2i are complex and remain to be investigated. In this study, we evaluated the direct biomechanical effects of SGLT2i empagliflozin on isolated myocardium from end-stage heart failure patients., Methods: Ventricular tissue biopsies obtained from 7 patients undergoing heart transplantation or ventricular assist device implantation surgery were cut into 27 living myocardial slices (LMS) and mounted in custom-made cultivation chambers with mechanical preload and electrical stimulation, resulting in cardiac contractions. These 300 µm thick LMS were subjected to 10 µM empagliflozin and with continuous recording of biomechanical parameters., Results: Empagliflozin did not affect the maximum contraction force of the slices, however, increased total contraction duration by 13% (p = 0.002) which was determined by prolonged time to peak and time to relaxation (p = 0.009 and p = 0.003, respectively)., Conclusion: The addition of empagliflozin to LMS from end-stage heart failure patients cultured in a biomimetic system improves contraction and relaxation kinetics by increasing total contraction duration without diminishing maximum force production. Therefore, we present convincing evidence that SGLT2i can directly act on the myocardium in absence of systemic influences from other organ systems., (© 2023. The Author(s).)

In this video, Javed Butler, MD, Jonathan Rich, MD, Rachel Pessah-Pollack, MD, and John E. Anderson, MD, summarize the key points of the enhanced publication "Role of SGLT2 Inhibitors in the Management of Heart Failure With and Without Type 2 Diabetes." The panel then delves deeper into some of the topics raised., Competing Interests: Funding Support and Author Disclosures Dr Butler is a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor; and a speaker for AstraZeneca, Boehringer Ingelheim, Impulse Dynamics, Merck, Novartis, and Vifor. Dr Rich is a consultant for Boehringer Ingelheim. Dr Pessah-Pollack is an advisor for Boehringer Ingelheim and Eli Lilly and an advisory board member for Health monitor. Dr Anderson has received consulting, advisory board, and speaker fees from Abbott Diabetes Care, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly and Company, Novo Nordisk, and Sanofi. Publication of this summary and digital supplement was supported by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI) and Lilly USA, LLC. Writing, editorial support, and creative assistance was provided by Envision Pharma Group, which was contracted and funded by BIPI and Lilly USA, LLC. The authors meet criteria for authorship as recommended by the ICMJE (International Committee of Medical Journal Editors). The authors received no payment related to the development of this summary or video. BIPI and Lilly were given the opportunity to review the summary and video storyboard for medical and scientific accuracy, as well as intellectual property considerations., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In this video, Javed Butler, MD, and Rachel Pessah-Pollack, MD, discuss the use of SGLT2 inhibitors in patients with and without type 2 diabetes., Competing Interests: Funding Support and Author Disclosures Dr Butler is a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor; and a speaker for AstraZeneca, Boehringer Ingelheim, Impulse Dynamics, Merck, Novartis, Vifor. Dr Pessah-Pollack is an advisor for Boehringer Ingelheim and Eli Lilly and an advisory board member for Health monitor. Publication of this summary and digital supplement was supported by Boehringer Ingelheim Pharmaceuticals, Inc (BIPI) and Lilly USA, LLC. Writing, editorial support, and creative assistance was provided by Envision Pharma Group, which was contracted and funded by BIPI and Lilly USA, LLC. The authors meet criteria for authorship as recommended by the ICMJE (International Committee of Medical Journal Editors). The authors received no payment related to the development of this summary or video. BIPI and Lilly were given the opportunity to review the summary and video storyboard for medical and scientific accuracy, as well as intellectual property considerations., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In this video, Javed Butler, MD, introduces the series on the use of SGLT2 inhibitors in heart failure. He discusses the epidemiology of heart failure and the effects of SGLT2 inhibitors on heart failure outcomes. Jonathan Rich, MD, joins to summarize the effects of SGLT2 inhibitors from dedicated trials in patients with heart failure., Competing Interests: Funding Support and Author Disclosures Dr Butler is a consultant for Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor; and a speaker for AstraZeneca, Boehringer Ingelheim, Impulse Dynamics, Merck, Novartis, and Vifor. Dr Rich is a consultant for Boehringer Ingelheim. Publication of this summary and digital supplement was supported by the Boehringer Ingelheim Pharmaceuticals, Inc (BIPI) and Lilly USA, LLC. Writing, editorial support, and creative assistance was provided by Envision Pharma Group, which was contracted and funded by BIPI and Lilly USA, LLC. The authors meet criteria for authorship as recommended by the ICMJE (International Committee of Medical Journal Editors). The authors received no payment related to the development of this summary or video. BIPI and Lilly were given the opportunity to review the summary and video storyboard for medical and scientific accuracy, as well as intellectual property considerations., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objective: Major adverse cardiovascular event (MACE) outcomes associated with sodium-glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide-1 receptor agonist (GLP-1 RA) therapies remain unclear in patients with type 2 diabetes and newly diagnosed diabetic foot complications (DFCs). This study examined the impact of SGLT2i and GLP-1 RA use on the rates of MACEs and amputations in patients with type 2 diabetes and without cardiovascular disease., Methods: Data from the Taiwan National Health Insurance Research Database (2004-2017) were analyzed, focusing on patients with type 2 diabetes without previous MACE and newly diagnosed DFCs. The primary outcome was the first MACE occurrence, and the secondary outcomes included MACE components, all-cause mortality, and lower extremity amputation (LEA) rates., Results: SGLT2i users showed a significant decrease in the MACE (hazard ratio [HR], 0.64; 95% confidence interval [CI], 0.46-0.88) and hospitalization for heart failure (HR, 0.54; 95% CI, 0.35-0.83) rates compared with dipeptidyl peptidase-4 inhibitor users. The amputation rates were also lower in SGLT2i users without LEA at the first DFC diagnosis (HR, 0.28; 95% CI, 0.10-0.75) and did not increase in those with a history of peripheral artery disease or LEA. No significant differences were observed between dipeptidyl peptidase-4 inhibitor and GLP-1 RA users in terms of the primary or secondary outcomes., Conclusion: In patients with type 2 diabetes initially diagnosed with DFC, SGLT2i are effective in significantly reducing the hospitalization for heart failure and MACE rates. SGLT2i lower the amputation rates, especially in patients who have not previously had a LEA, than the dipeptidyl peptidase-4 inhibitor therapy., Competing Interests: Disclosure The authors have no conflicts of interest to disclose., (Copyright © 2024 AACE. Published by Elsevier Inc. All rights reserved.)

Objective: To evaluate the role of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with preserved ejection fraction (HFpEF)., Data Sources: A literature search of PubMed, the Cochrane Library, and Google Scholar databases (January 2015 to June 20, 2023) was performed with keywords: sodium-glucose co-transporter 2 inhibitors OR SGLT2 inhibitors OR bexagliflozin OR canagliflozin OR dapagliflozin OR empagliflozin OR ertugliflozin OR sotagliflozin AND heart failure OR heart failure with preserved ejection fraction, and terms related to CV outcomes including cardiovascular death, hospitalization, hospitalization for heart failure, mortality, death, and major adverse cardiovascular event (MACE)., Study Selection and Data Extraction: The reference list from retrieved articles as well as relevant review articles was considered. Pivotal randomized controlled trials and meta-analyses with a primary or secondary end point of CV death or heart failure hospitalization were included. Studies conducted solely in a diabetic patient population were excluded., Data Synthesis: Dapagliflozin and empagliflozin, in a broad population of heart failure patients including, HFrEF, HFmrEF, HFpEF, and without diabetes, have shown consistent improvement in the combined outcome of CV death and hospitalization for heart failure (HR 0.80, 95% CI 0.73-0.87) and in the reduction of heart failure hospitalizations (HR 0.74, 95% CI 0.67-0.83). In patients with HFpEF, cardiovascular mortality was not demonstrated (HR 0.88, 95% CI 0.77-1.00). Rates of adverse events were low., Relevance to Patient Care and Clinical Practice: Patients with HFpEF and NYHA class II-III with frequent symptoms or hospitalizations for heart failure derive the most benefit from SGLT2 inhibitors with an overall goal of a reduction in heart failure hospitalizations., Conclusions: The treatment of HFpEF has made progress, but there is still work to be done. Now, SGLT2 inhibitor therapy can be used to further help with symptom control and reduce overall hospitalizations for heart failure., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Cardiovascular diseases are caused by pathological cardiac remodeling, which involves fibrosis, inflammation and cell dysfunction. This includes autophagy, apoptosis, oxidative stress, mitochondrial dysfunction, changes in energy metabolism, angiogenesis and dysregulation of signaling pathways. These changes in heart structure and/or function ultimately result in heart failure. In an effort to prevent this, multiple cardiovascular outcome trials have demonstrated the cardiac benefits of sodium‑glucose cotransporter type 2 inhibitors (SGLT2is), hypoglycemic drugs initially designed to treat type 2 diabetes mellitus. SGLT2is include empagliflozin and dapagliflozin, which are listed as guideline drugs in the 2021 European Guidelines for Heart Failure and the 2022 American Heart Association/American College of Cardiology/Heart Failure Society of America Guidelines for Heart Failure Management. In recent years, multiple studies using animal models have explored the mechanisms by which SGLT2is prevent cardiac remodeling. This article reviews the role of SGLT2is in cardiac remodeling induced by different etiologies to provide a guideline for further evaluation of the mechanisms underlying the inhibition of pathological cardiac remodeling by SGLT2is, as well as the development of novel drug targets.

Sodium-glucose cotransporter-2 inhibitors (SGLT2is) have been shown to reduce adverse cardiovascular events in patients with type 2 diabetes mellitus, all-cause mortality, and heart failure hospitalization in patients with heart failure, as well as adverse renal outcomes. However, concerns regarding the heightened risk of genitourinary (GU) infections, particularly urinary tract infections, remain a significant barrier to their wider adoption. Addressing these misconceptions using existing evidence is needed to ensure proper risk-benefit assessment and optimal utilization of this efficacious therapy. This review aims to provide a balanced perspective on the evidence-based cardiovascular and renal benefits of SGLT2is and the associated risk of GU infections. We also summarize and propose clinical practice considerations for SGLT2i-associated GU infections focusing on patients with cardiovascular disease., Competing Interests: Funding Support and Author Disclosures Dr Cox has received grants from AstraZeneca; and has received personal fees from Abiomed, ROCHE, and Translational Catalyst. Dr Lindenfeld is a consultant for Abbott, ADI, Alleviant, Amgen, AstraZeneca, Axon, Boston Scientific, Cordio, CVRx, Cytokinetics, Edwards Lifesciences, Medtronic, Merck, VWave, Vascular Dynamics, Vectorious, and Whiteswell; and has received grants from Analog Devices Inc, AstraZeneca, and Volumetrix. Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Fast BioMedical, Gilead, Innolife, Eli Lilly, Medtronic, Medable, Merck, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Relypsa, Respicardia, Roche, Rocket Pharmaceuticals, Sanofi, Verily, Vifor, Windtree Therapeutics, and Zoll. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are now indicated for heart failure and chronic kidney disease (CKD), irrespective of the presence of diabetes. Hence, cardiologists and nephrologists have an important role in initiating these drugs., Aims: To explore cardiologists' and nephrologists' perspectives regarding initiating SGLT2i and their safety monitoring practices when initiating SGLT2i., Methods: Purposive and snowball approaches were used to recruit participants working in diverse areas in New South Wales, Australia. Semi-structured interviews were conducted with 12 cardiologists and 12 nephrologists. Interviews were conducted until thematic saturation was reached. Emergent themes were identified from transcripts. An iterative general inductive approach was used for data analysis., Results: There was a reluctance amongst most non-heart-failure subspecialist cardiologists to initiate SGLT2i. Reasons included the perception of SGLT2i as diabetes drugs, concern about side effects, lack of experience and issues with follow-up. In contrast, nephrologists reported feeling confident to initiate SGLT2i. Nephrologists varied in their opinions about the severity of CKD at which SGLT2i initiation was reasonable and monitoring of renal function following initiation. Government subsidisation was an important factor in the decision to prescribe SGLT2i to people without diabetes., Conclusions: Our findings highlight the complex transition from the perception of SGLT2i as diabetes drugs to cardiometabolic and reno-protective agents. Interdisciplinary collaboration may enable greater confidence amongst specialists to initiate SGLT2i, including in patients with CKD. Additionally, there is a need for clear and detailed guidance about SGLT2i prescription in patients with renal dysfunction and renal function monitoring following SGLT2i initiation., (© 2023 The Authors. Internal Medicine Journal published by John Wiley & Sons Australia, Ltd on behalf of Royal Australasian College of Physicians.)

Aims: Patients with heart failure and reduced ejection fraction (HFrEF) exhibit skeletal muscle pathology, which contributes to symptoms and decreased quality of life. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) improve clinical outcomes in HFrEF but their mechanism of action remains poorly understood. We aimed, therefore, to determine whether SGLT2i influence skeletal muscle pathology in patients with HFrEF., Methods and Results: Muscle biopsies from 28 male patients with HFrEF (New York Heart association class I-III) treated with SGLT2i (>12 months) or without SGLT2i were compared. Comprehensive analyses of muscle structure (immunohistochemistry), transcriptome (RNA sequencing), and metabolome (liquid chromatography-mass spectrometry) were performed, and serum inflammatory profiling (ELISA). Experiments in mice (n = 16) treated with SGLT2i were also performed. Myofiber atrophy was ~20% less in patients taking SGLT2i (p = 0.07). Transcriptomics and follow-up measures identified a unique signature in patients taking SGLT2i related to beneficial effects on atrophy, metabolism, and inflammation. Metabolomics identified influenced tryptophan metabolism in patients taking SGLT2i: kynurenic acid was 24% higher and kynurenine was 32% lower (p < 0.001). Serum profiling identified that SGLT2i treatment was associated with lower (p < 0.05) pro-inflammatory cytokines by 26-64% alongside downstream muscle interleukin (IL)-6-JAK/STAT3 signalling (p = 008 and 0.09). Serum IL-6 and muscle kynurenine were correlated (R = 0.65; p < 0.05). Muscle pathology was lower in mice treated with SGLT2i indicative of a conserved mammalian response to treatment., Conclusions: Treatment with SGLT2i influenced skeletal muscle pathology in patients with HFrEF and was associated with anti-atrophic, anti-inflammatory, and pro-metabolic effects. These changes may be regulated via IL-6-kynurenine signalling. Together, clinical improvements following SGLT2i treatment in patients with HFrEF may be partly explained by their positive effects on skeletal muscle pathology., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Patients with heart failure (HF) and history of myocardial infarction (MI) face a higher risk of disease progression and clinical events. Whether sodium-glucose cotransporter 2 inhibitors may modify clinical trajectory in such individuals remains incompletely understood., Methods and Results: The DAPA-HF and DELIVER trials compared dapagliflozin with placebo in patients with symptomatic HF with left ventricular ejection fraction (LVEF) ≤40% and > 40%, respectively. In this pooled participant-level analysis, we assessed efficacy and safety outcomes by history of MI. The primary outcome in both trials was the composite of cardiovascular death or worsening HF. Of the total of 11 007 patients, 3731 (34%) had a previous MI and were at higher risk of the primary outcome across the spectrum of LVEF in covariate-adjusted models (hazard ratio [HR] 1.12, 95% confidence interval [CI] 1.02-1.24). Dapagliflozin reduced the risk of the primary outcome to a similar extent in patients with (HR 0.83, 95% CI 0.72-0.96) and without previous MI (HR 0.76, 95% CI 0.68-0.85; p interaction  = 0.36), with consistent benefits on key secondary outcomes as well. Serious adverse events did not occur more frequently with dapagliflozin, irrespective of previous MI., Conclusion: History of MI confers increased risks of adverse cardiovascular outcomes in patients with HF across the LVEF spectrum, even among those with preserved ejection fraction. Dapagliflozin consistently and safely reduces the risk of cardiovascular death or worsening HF, regardless of previous MI., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Although beta-blockers are not recommended for the treatment of heart failure with preserved ejection fraction (HFpEF) according to the latest European Society of Cardiology and American Heart Association/American College of Cardiology/Heart Failure Society of America guidelines, these therapies remain commonly used for comorbidity management. There has been concern that beta-blockers may adversely influence clinical outcomes by limiting chronotropic response in HFpEF., Objectives: This study sought to examine the contemporary use and implications of beta-blockers in patients with heart failure with mildly reduced ejection fraction (HFmrEF) or HFpEF., Methods: In the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, a total of 6,263 patients with symptomatic heart failure (HF) with a left ventricular ejection fraction (LVEF) >40% were randomized to dapagliflozin or placebo across 20 countries. In this prespecified analysis, efficacy and safety outcomes were examined according to beta-blocker use at randomization. The primary outcome was cardiovascular death or worsening HF., Results: Overall, beta-blockers were used in 5,177 patients (83%), with wide variation by geographic region. Beta-blocker use was associated with a lower risk of the primary outcome in covariate-adjusted models (HR: 0.70; 95% CI: 0.60-0.83). Dapagliflozin consistently reduced the risk of the primary outcome in patients taking beta-blockers (HR: 0.82; 95% CI: 0.72-0.94) and in patients not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03; P interaction  = 0.85), with similar findings for key secondary endpoints. Adverse events were balanced between patients randomized to dapagliflozin and placebo, regardless of background beta-blocker use., Conclusions: In patients with HFmrEF or HFpEF who were enrolled in DELIVER, 4 out of 5 participants were treated with a beta-blocker. Beta-blocker use was not associated with a higher risk of worsening HF or cardiovascular death. Dapagliflozin consistently and safely reduced clinical events, irrespective of background beta-blocker use. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures The DELIVER trial was funded by AstraZeneca. Dr Peikert has received a research grant from the German Research Foundation. Dr Bart has received research grant support (paid to institution) from AstraZeneca, Cardurion, and Daxor; and has participated in clinical trial committees for studies sponsored by Daxor and Nuwellis. Dr Vaduganathan has received research grant support, served on advisory boards, or had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, Intellia, and Rocket. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35 Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received institutional research grants from Abbott, AstraZeneca, Alnylam, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, AstraZeneca, Alnylam, Avidity, Axon Therapeutics, Bayer, Biofourmis, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, River2Renal, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; has received personal fees from Roche and Intas Pharma; has served as Director of Global Clinical Trial Partners (GCTP); and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and Novo Nordisk. Dr Lam has received supported from a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board/steering committee/executive committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development, Medscape/WebMD Global, Merck, Novartis, Novo Nordisk, Prosciento, Radcliffe Group, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and us2.ai; and has served as cofounder and nonexecutive director of us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol-Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic and Verily; and has served as a consultant or on the advisory board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Eli Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Petersson is an employee and shareholder of AstraZeneca. Dr Langkilde is an employee and shareholder of AstraZeneca. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting, and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GlaxoSmithKline, KBP Biosciences, and Novartis; has received personal consulting fees from Alnylam Pharma, Bayer, Bristol-Myers Squibb, George Clinical PTY, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; has received personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals and Pharma, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, Translational Medicine Academy; and has served as a director of Global Clinical Trial Partners. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol-Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, and us2.ai; and has served as a consultant for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. Dr Vardeny has received research support from AstraZeneca, Bayer, and Cardurion; and has received personal consulting fees from Cardior. Mr Kulac has reported that he has no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The sodium glucose cotransporter-2 inhibitors are guideline-recommended to treat heart failure across the spectrum of left ventricular ejection fraction; however, economic evaluations of adding sodium glucose cotransporter-2 inhibitors to standard of care in chronic heart failure across a broad left ventricular ejection fraction range are lacking., Methods and Results: We conducted a US-based cost-effectiveness analysis of dapagliflozin added to standard of care in a chronic heart failure population using pooled, participant data from the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials. The 3-state Markov model used estimates of transitional probabilities, effectiveness of dapagliflozin, and utilities from the pooled trials. Costs estimates were obtained from published sources, including published rebates in dapagliflozin cost. Adding dapagliflozin to standard of care was estimated to produce an additional 0.53 quality-adjusted life years (QALYs) compared with standard of care alone. Incremental cost effectiveness ratios were $85 554/QALY when using the publicly reported full (undiscounted) Medicare cost ($515/month) and $40 081/QALY, at a published nearly 50% rebate ($263/month). The addition of dapagliflozin to standard of care would be of at least intermediate value (<$150 000/QALY) at a cost of <$872.58/month, of high value (<$50 000/QALY) at <$317.66/month, and cost saving at <$40.25/month. Dapagliflozin was of at least intermediate value in 92% of simulations when using the full (undiscounted) Medicare list cost in probabilistic sensitivity analyses. Cost effectiveness was most sensitive to the dapagliflozin cost and the effect on cardiovascular death., Conclusions: The addition of dapagliflozin to standard of care in patients with heart failure across the spectrum of ejection fraction was at least of intermediate value at the undiscounted Medicare cost and may be potentially of higher value on the basis of the level of discount, rebates, and price negotiations offered., Registration: URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01035255 & NCT01920711.

Sodium-glucose cotransporter-2 inhibitors have been shown to have significant metabolic, renal, and atherosclerotic cardiovascular disease benefits. Recent randomized controlled trials have extended these benefits to patients with heart failure. In fact, the robust findings from these studies in patients with any type of heart failure have led to the incorporation of this drug class in currently updated evidence-based guidelines for this condition. However, given the novelty in utilizing these agents in heart failure, there is uncertainty regarding place in therapy and sequencing in treatment. As such, this review aims to summarize existing literature to guide practitioners regarding the use of these agents in the management of heart failure., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2i) are one of the cornerstones of heart failure (HF) therapy. While benefits in terms of HF hospitalizations and death are well established, their impact on quality-of-life (QoL) has not been systematically investigated., Objective: This systematic review and meta-analysis aims to evaluate the impact of SGLT2i treatment on QoL in patients with HF, by analysing data from randomized clinical trials (RCTs)., Methods: We identified a total of 23 RCTs that investigated the role of SGLT2i on quality of life in patients with HF, irrespective of their left ventricular ejection fraction (LVEF). RCTs that used Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) to assess QoL and had a minimum follow-up of 3 months were included. The difference in mean change of the KCCQ-OSS between the SGLT2i group and the standard of care (SOC) group at 3 and 6 months from baseline was considered as the outcome measure., Findings: Fourteen RCTs (21 737 patients) were included in the analysis. A significant improvement in KCCQ-OSS over time (p < 0.001) was observed in both patients receiving SOC and those receiving SGLT2i in addition. The pooled estimate showed a significant improvement of 1.94 points [95% confidence interval (CI), 1.41-2.46] in KCCQ-OSS mean change at 3 months and of 2.18 points (95% CI, 1.13-3.24) at 6 months from baseline, with SGLT2i compared to SOC alone, irrespective of LVEF. A greater improvement in KCCQ-OSS was observed among patients with a recent episode of worsening HF compared to those with chronic stable HF., Conclusions: Among patients with HF, irrespective of their LVEF and clinical status, the addition of SGLT2i to SOC demonstrated a significant improvement in quality of life as early as at 3-month follow-up., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: To investigate the individual profile of each SGLT2 (sodium-glucose cotransoporter-2) inhibitor in patients with different backgrounds., Methods and Results: This study included 21 placebo-controlled randomized controlled trials with a total of 96 196 participants, investigating empagliflozin, ertugliflozin, dapagliflozin, canagliflozin, and sotagliflozin. The primary efficacy end point was the composite of cardiovascular death and hospitalizations for heart failure. The secondary efficacy end points were all-cause death, cardiovascular death, hospitalizations for heart failure, kidney disease progression, and acute kidney injury. We conducted subgroup analyses based on the underlying comorbidities, including diabetes and chronic kidney disease. Safety end points were also assessed among SGLT2 inhibitors in the overall cohort. In the overall cohort, there were no significant differences in the primary efficacy outcome among the SGLT2 inhibitors, while empagliflozin (hazard ratio [HR], 0.70 [95% CI, 0.53-0.92]) and dapagliflozin (HR, 0.73 [95% CI, 0.56-0.96]) were associated with lower risk of acute kidney injury than sotagliflozin. The presence or absence of diabetes did not alter the results. In patients with chronic kidney disease, there were no differences in the efficacy outcomes among SGLT2 inhibitors, while in patients without chronic kidney disease, empagliflozin was associated with lower risk of the primary outcome compared with ertugliflozin (HR, 0.77 [95% CI, 0.60-0.98]). For safety outcomes, no significant differences were observed in amputation, urinary tract infection, genital infection, hypoglycemia, and diabetic ketoacidosis., Conclusions: The differences in reducing cardiovascular and kidney outcomes as well as safety profiles across SGLT2 inhibitors were not consistently significant, although empagliflozin might be preferred in patients without chronic kidney disease. Further investigations are needed to better understand the mechanism and clinical effectiveness of each SGLT2 inhibitor in certain populations.

Background: Frailty is a severe, common co-morbidity associated with heart failure (HF) with preserved ejection fraction (HFpEF). The impact of frailty on HFpEF outcomes may affect treatment choices in HFpEF. The impact of frailty on HFpEF patients and any impact on the clinical benefits of sodium glucose co-transporter 2 (SGLT2) inhibition in HFpEF have been described in only a limited number of trials. Whether the SGLT2 inhibitor empagliflozin would improve or worsen frailty status when given to HFpEF patients is also not known. The aims of this study were, therefore, to evaluate, in HFpEF patients enrolled in the EMPEROR-Preserved trial (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction), the impact of frailty on clinical outcomes, and on the effects of empagliflozin, as well as the effect of empagliflozin on frailty status during treatment period., Methods: We calculated a cumulative deficit-derived frailty index (FI) using 44 variables including clinical, laboratory and quality of life parameters recorded in EMPEROR-Preserved. Patients were classified into four groups: non-frail (FI < 0.21), mild frailty (0.21 to <0.30), moderate frailty (0.30 to <0.40) and severe frailty (≥0.40). Clinical outcomes and health-related quality of life were evaluated according to baseline FI along with the effect of empagliflozin on chronological changes in FI (at 12, 32 and 52 weeks)., Results: The patient distribution was 1514 (25.3%), 2100 (35.1%), 1501 (25.1%) and 873 (14.6%) in non-frail, mild frailty, moderate frailty and severe frailty, respectively. Severe frailty patients tended to be female and have low Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, more co-morbidities and more polypharmacy. Incidence rates of the primary outcome of cardiovascular death or HF hospitalization increased as frailty worsened (hazard ratio [HR] of each FI category compared with the non-frail group: 1.10 [95% confidence interval, CI, 0.89-1.35], 2.00 [1.63-2.47] and 2.61 [2.08-3.27] in the mild frailty, moderate frailty and severe frailty groups, respectively; P trend < 0.001). Compared with placebo, empagliflozin reduced the risk for the primary outcome across the four FI categories, HR: 0.59 [95% CI 0.42-0.83], 0.79 [0.61-1.01], 0.77 [0.61-0.96] and 0.90 [0.69-1.16] in non-frail to severe frailty categories, respectively (P value for trend = 0.097). Empagliflozin also improved other clinical outcomes and KCCQ score across frailty categories. Compared with placebo, empagliflozin-treated patients had a higher likelihood of being in a lower FI category at Weeks 12, 32 and 52 (P < 0.05), odds ratio: 1.12 [95% CI 1.01-1.24] at Week 12, 1.21 [1.09-1.34] at Week 32 and 1.20 [1.09-1.33] at Week 52., Conclusions: Empagliflozin improved key efficacy outcomes with a possible diminution of effect in very frail patients. Empagliflozin also improved frailty status during follow-up., (© 2023 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by Wiley Periodicals LLC.)

Aim: Cardiac remodelling plays a major role in the prognosis of patients with aortic stenosis (AS) and could impact the benefits of aortic valve replacement. Our study aimed to evaluate the expression of sodium-glucose cotransporter 2 (SGLT2) gene and protein in patients with severe AS stratified in high gradient (HG) and low flow-low gradient (LF-LG) AS and its association with cardiac functional impairments., Methods and Results: Gene expression and protein levels of main biomarkers of cardiac fibrosis (galectin-3, sST2, serpin-4, procollagen type I amino-terminal peptide, procollagen type I carboxy-terminal propeptide, collagen, transforming growth factor [TGF]-β), inflammation (growth differentiation factor-15, interleukin-6, nuclear factor-κB [NF-κB]), oxidative stress (superoxide dismutase 1 [SOD1] and 2 [SOD2]), and cardiac metabolism (sodium-hydrogen exchanger, peroxisome proliferator-activated receptor [PPAR]-α, PPAR-γ, glucose transporter 1 [GLUT1] and 4 [GLUT4]) were evaluated in blood samples and heart biopsies of 45 patients with AS. Our study showed SGLT2 gene and protein hyper-expression in patients with LF-LG AS, compared to controls and HG AS (p < 0.05). These differences remained significant even after adjusting for age, gender, body mass index, history of diabetes mellitus, arterial hypertension, and coronary artery disease. SGLT2 gene expression was positively correlated with: (i) TGF-β (r = 0.72, p < 0.001) and collagen (r = 0.73, p < 0.001) as markers of fibrosis; (ii) NF-κB (r = 0.36, p < 0.01) and myocardial interleukin-6 (r = 0.68, p < 0.001) as markers of inflammation: (iii) SOD2 (r = -0.38, p < 0.006) as a marker of oxidative stress; (iv) GLUT4 (r = 0.33, p < 0.02) and PPAR-α (r = 0.36, p < 0.01) as markers of cardiac metabolism., Conclusion: In patients with LF-LG AS, SGLT2 gene and protein were hyper-expressed in cardiomyocytes and associated with myocardial fibrosis, inflammation, and oxidative stress., (© 2024 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved empagliflozin for reducing cardiovascular mortality and heart failure (HF) hospitalization in patients with both HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). However, limited data are available on the generalizability of empagliflozin to clinical practice. Therefore, we evaluated real-world eligibility and potential cost-effectiveness based on a nationwide prospective HF registry., Methods: A total of 3,108 HFrEF and 2,070 HFpEF patients from the Korean Acute Heart Failure (KorAHF) registry were analyzed. Eligibility was estimated by inclusion and exclusion criteria of EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Reduced Ejection Fraction (EMPEROR-Reduced) and EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved) trials and by FDA & EMA label criteria. The cost-utility analysis was done using a Markov model to project the lifetime medical cost and quality-adjusted life year (QALY)., Results: Among the KorAHF patients, 91.4% met FDA & EMA label criteria, while 44.7% met the clinical trial criteria. The incremental cost-effectiveness ratio of empagliflozin was calculated at US$6,764 per QALY in the overall population, which is far below a threshold of US$18,182 per QALY. The cost-effectiveness benefit was more evident in patients with HFrEF (US$5,012 per QALY) than HFpEF (US$8,971 per QALY)., Conclusion: There is a large discrepancy in real-world eligibility for empagliflozin between FDA & EMA labels and clinical trial criteria. Empagliflozin is cost-effective in HF patients regardless of ejection fraction in South Korea health care setting. The efficacy and safety of empagliflozin in real-world HF patients should be further investigated for a broader range of clinical applications., Trial Registration: ClinicalTrials.gov Identifier: NCT01389843., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

Purpose: Numerous clinical studies have explored sodium-glucose cotransporter 2 inhibitor (SGLT2i) in patients with chronic heart failure (CHF), with or without type 2 diabetes mellitus (T2DM), and SGLT2i were proved to significantly reduce CHF hospitalization, cardiovascular death, cardiovascular mortality, all-cause mortality and myocardial infarction in patients with or without T2DM. However, only a limited few have investigated the effects of SGLT-2i on HF disease-specific health status and cardiac function. This meta-analysis aims to assess the effects of SGLT2i on disease-specific health status and cardiac function in CHF patients., Methods: A comprehensive search was conducted of trials by searching in PubMed, EMBASE, CENTRAL, Scopus, and Web of Science, and two Chinese databases (CNKI and Wanfang), Clinical Trials ( http://www., Clinicaltrials: gov ) were also searched., Results: A total of 18 randomized controlled trials (RCTs) involving 23,953 participants were included in the meta-analysis. The effects of SGLT2 inhibitors were compared with control or placebo groups in CHF with or without T2DM. The SGLT2 inhibitors group exhibited a significant reduction in pro b-type natriuretic peptide (NT-proBNP) levels by 136.03 pg/ml (95% confidence interval [CI]: -253.36, - 18.70; P = 0.02). Additionally, a greater proportion of patients in the SGLT2 inhibitors group showed a ≥ 20% decrease in NT-proBNP (RR = 1.45, 95% CI [0.92, 2.29], p = 0.072). However, no statistically significant difference was observed for the effects on B-type natriuretic peptide (BNP). The use of SGLT-2 inhibitors led to a noteworthy improvement in LVEF by 2.79% (95% CI [0.18, 5.39];P = 0.036). In terms of health status, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance, SGLT2 inhibitors led to a significant improvement in KCCQ clinical summary (KCCQ-CS) score (WMD = 1.7, 95% CI [1.67, 1.73], P < 0.00001), KCCQ overall summary (KCCQ-OS) score (WMD = 1.73, 95% CI [0.94, 2.52], P < 0.00001), and KCCQ total symptom (KCCQ-TS) score (WMD = 2.88, 95% CI [1.7, 4.06], P < 0.00001). Furthermore, the occurrence of KCCQ-CS and KCCQ-OS score increases ≥ 5 points had relative risks (RR) of 1.25 (95% CI [1.11, 1.42], P < 0.00001) and 1.15 (95% CI [1.09, 1.22], P < 0.00001), respectively. Overall, SGLT2 inhibitors increased the 6-minute walk distance by 23.98 m (95% CI [8.34, 39.62]; P = 0.003) compared to control/placebo from baseline., Conclusions: The SGLT2 inhibitors treatment offers an effective strategy for improving NT-proBNP levels, Kansas City Cardiomyopathy Questionnaire scores and 6-minute walk distance in CHF with or without T2DM. These findings indicate that SGLT2i improve cardiac function and health status in CHF with or without T2DM, and provide valuable guidance for clinicians making treatment decisions for patients with CHF., (© 2023. The Author(s).)

Background: Heart failure (HF) is a highly prevalent disease, among the primary factors contributing to morbidity and death. One of its types is heart failure with preserved ejection fraction (HFpEF) comprising 40%-50% of newly diagnosed HF cases. Despite the high prevalence of HFpEF, there is still a lack of knowledge regarding the best drugs and treatment approaches to be used. However, the sodium-glucose co-transporter 2 (SGLT2) inhibitors could be a promising treatment., Objectives: To examine SGLT2 inhibitors' effect on hospitalization, cardiovascular death, and estimated glomerular filtration rate (eGFR) in HFpEF patients., Search Methods: We conducted searches for randomized controlled trials (RCTs) in PubMed, Embase, Scopus, and Web of Science up to July 2024., Selection Criteria: We chose RCTs that examined the effects of SGLT2 inhibitors and placebo in individuals with higher than 40% ejection fraction (HFpEF)., Data Collection and Analysis: The methodology for the systematic review and meta-analysis was in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis., Main Results: We included 8 studies with 16,509 participants. Drugs examined in our paper included empagliflozin, dapagliflozin, sotogliflozin, and ertugliflozin. Various outcomes were analyzed in different papers. However, different SGLT2 inhibitors lead to a decreased risk of cardiovascular hospitalization and kidney injury. Our meta-analysis showed a decreased risk of cardiovascular hospitalization but not death due to cardiovascular causes or other causes. These results were regardless of baseline status of eGFR, systolic blood pressure, atrial fibrillation or flutter, diabetes mellitus, sex, body mass index, and nt-proBNP. The included studies were of moderate to high quality., Conclusion: For individuals with HFpEF, SGLT2 inhibitors have been proven to be a safe and effective medication. However, more studies are needed for longer durations, reporting adverse events, effects on exercise tolerance, and other secondary outcomes.

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is reported to reduce incident atrial fibrillation (AF) in patients with or without diabetes; however, its cardiovascular (CV) benefit for AF patients remains unclear., Ss Aims: To investigate the effect of SGLT2i on the incidence of CV events in patients with AF., Methods: Six randomized controlled trials (RCTs) assessing the effects of SGLT2i on CV outcomes in patients with or without AF were included (PROSPERO: CRD 42023431535). The primary endpoint was the composite outcome of heart failure (HF) hospitalization and CV death. Additionally, we assessed the effects of treatment in prespecified subgroups on HF hospitalization, CV death, and all-cause mortality., Results: Among 38,529 participants from all trials, 5018 patients with AF were treated with SGLT2i. The follow-up period of these trials ranged from 2.3 to 3.3 years. SGLT2i treatment was significantly associated with the risk reduction of primary endpoint in patients with AF (risk ratio [RR] 0.81, 95% confidence interval [CI] 0.74-0.88; p < 0.001), consistent with the finding in the general population (p for interaction = 0.76). SGLT2i was also associated with a consistent reduction in the risk of HF hospitalization in patients with AF (RR 0.76, 95% CI 0.69-0.84; p < 0.001) or not (RR 0.72, 95% CI 0.64-0.80; p < 0.0001), with no statistical difference between them (p for interaction = 0.41). Meta-regression further revealed no significant association between the prevalence of HF with reduced ejection fraction or diabetes and the effect size of SGLT2i., Conclusions: The treatment effects of SGLT2i were associated with a lower incidence of CV events, especially HF hospitalization, in patients with AF., (© 2023 Wiley Periodicals LLC.)

Background: SGLT2 inhibitors have been shown to reduce hospitalisation in patients with chronic heart failure (CHF). The cardioprotective mechanisms of gliflozins however have not been fully elucidated. The aim of this study was therefore to evaluate the effect of SGLT2 inhibitors on right and left ventricular function in patients with diabetes and HF., Methods: Seventy-eight patients with diabetes and CHF were enroled in the study and followed up; 38 started treatment with SGLT2i, while the remaining 40 continued their previous antidiabetic therapy. All patients underwent conventional, TDI and strain echocardiography in an ambulatory setting, at the beginning and after 3 months of therapy with SGLT2i., Results: After 3 months of therapy with SGLT2i, echocardiographic parameters assessing both left and right ventricular dimensions and function were found as significantly improved in patients switching to SGLT2i than control group: LVEF (45 ± 9% vs. 40 ± 8%, p < 0.001), LVEDD (54 ± 6.5 vs. 56 ± 6.5 mm, p < 0.01), GLS (-13 ± 4% vs. -10 ± 3%, p < 0.001), TAPSE (21 ± 3 vs. 19 ± 3 mm, p < 0.001), RV S' (12.9 ± 2.5 vs 11.0 ± 1.9 cm/sec, p < 0.001) and PAsP (24 ± 8 vs. 31 ± 9 mmHg, p < 0.001). Also mitral (1.0 ± 0.5 vs. 1.3 ± 0.5, p < 0.01) and tricuspid regurgitation (1.0 ± 0.5 vs. 1.3 ± 0.5, p < 0.01) improved after SGLT2i therapy. Changes were not statistically significant in patients not treated with SGLT2i (p n.s. in all cases)., Conclusions: In a real-world scenario, treatment with SGLT2i in patients with CHF and diabetes is associated with an improvement in both left and right ventricular function assessed at echocardiography. These data may explain potential anti-remodelling effects of gliflozins., (© 2023 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Purpose: This study was to investigate the association between the use of Sodium-glucose Cotransporter-2 inhibitors (SGLT2i) or angiotensin receptor-neprilysin inhibitor (ARNI; ie, Sacubitril + valsartan, Product name ENTRESTO) and the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with coexisting diabetes and heart failure. Specifically, the study compared outcomes between patients using SGLT2i or valsartan + sacubitril and those not using these medications., Methods: This study utilized data from the National Health Insurance Research Database (NHIRD) from 2017 to 2018. The case group consisted of 8691 patients with coexisting diabetes and heart failure who did not use SGLT2i or Entresto, while the control group consisted of 8691 patients with coexisting diabetes and heart failure who used SGLT2i or Entresto. The primary outcome was ASCVD, including a composite of cardiovascular death and hospitalization for worsening heart failure. Secondary outcomes included all-cause death, cause of cardiovascular death, and recurrence of heart failure, non-fatal myocardial infarction, non-fatal stroke (including ischemic stroke and hemorrhagic stroke) and new renal replacement therapy., Results: The study found that the use of SGLT2 inhibitors or ARNI was associated with a lower risk of ASCVD in patients with coexisting diabetes and heart failure., Conclusion: The study suggests that the use of SGLT2 inhibitors, alone or in combination with Entresto, may be effective in reducing the risk of ASCVD and its associated adverse outcomes in patients with diabetes and heart failure. This finding has important implications for the management of these conditions., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Certain antineoplastic therapies are associated with an increased risk of cardiomyopathy and heart failure (HF). Sodium glucose co-transporter 2 (SGLT2) inhibitors improve outcomes in patients with HF., Objectives: This study aims to examine the efficacy of SGLT2 inhibitors in patients with cancer therapy-related cardiac dysfunction (CTRCD) or HF., Methods: The authors conducted a retrospective cohort analysis of deidentified, aggregate patient data from the TriNetX research network. Patients aged ≥18 years with a history of type 2 diabetes mellitus, cancer, and exposure to potentially cardiotoxic antineoplastic therapies, with a subsequent diagnosis of cardiomyopathy or HF between January 1, 2013, and April 30, 2020, were identified. Patients with ischemic heart disease were excluded. Patients receiving guideline-directed medical therapy were divided into 2 groups based on SGLT2 inhibitor use. After propensity score matching, odds ratios (ORs) and Cox proportional HRs were used to compare outcomes over a 2-year follow-up period., Results: The study cohort included 1,280 patients with CTRCD/HF (n = 640 per group; mean age: 67.6 years; 41.6% female; 68% White). Patients on SGLT2 inhibitors in addition to conventional guideline-directed medical therapy had a lower risk of acute HF exacerbation (OR: 0.483 [95% CI: 0.36-0.65]; P < 0.001) and all-cause mortality (OR: 0.296 [95% CI: 0.22-0.40]; P = 0.001). All-cause hospitalizations or emergency department visits (OR: 0.479; 95% CI: 0.383-0.599; P < 0.001), atrial fibrillation/flutter (OR: 0.397 [95% CI: 0.213-0.737]; P = 0.003), acute kidney injury (OR: 0.486 [95% CI: 0.382-0.619]; P < 0.001), and need for renal replacement therapy (OR: 0.398 [95% CI: 0.189-0.839]; P = 0.012) were also less frequent in patients on SGLT2 inhibitors., Conclusions: SGLT2 inhibitor use is associated with improved outcomes in patients with CTRCD/HF., Competing Interests: Funding Support and Author Disclosures Dr Deswal is supported in part by the Ting Tsung and Wei Fung Chao Distinguished Chair. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

There is a bidirectional pathophysiological interaction between the heart and the kidneys, and prolonged physiological stress to the heart and/or the kidneys can cause adverse cardiorenal complications, including but not limited to subclinical cardiomyopathy, heart failure and chronic kidney disease. Whilst more common in individuals with Type 2 diabetes, cardiorenal complications also occur in the absence of diabetes. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) were initially approved to reduce hyperglycaemia in patients with Type 2 diabetes. Recently, these agents have been shown to significantly improve cardiovascular and renal outcomes in patients with and without Type 2 diabetes, demonstrating a robust reduction in hospitalisation for heart failure and reduced risk of progression of chronic kidney disease, thus gaining approval for use in treatment of heart failure and chronic kidney disease. Numerous potential mechanisms have been proposed to explain the cardiorenal effects of SGLT2i. This review provides a simplified summary of key potential cardiac and renal mechanisms underlying the cardiorenal benefits of SGT2i and explains these mechanisms in the clinical context. Key mechanisms related to the clinical effects of SGLT2i on the heart and kidneys explained in this publication include their impact on (1) tissue oxygen delivery, hypoxia and resultant ischaemic injury, (2) vascular health and function, (3) substrate utilisation and metabolic health and (4) cardiac remodelling. Knowing the mechanisms responsible for SGLT2i-imparted cardiorenal benefits in the clinical outcomes will help healthcare practitioners to identify more patients that can benefit from the use of SGLT2i., (© 2023. The Author(s).)

Purpose: Sodium glucose cotransporter 2 (SGLT2) inhibitors have been demonstrated to reduce cardiovascular deaths and heart failure (HF) hospitalizations in patients with HF. Despite this, utilization remains low. The purpose of this study was to characterize SGLT2 inhibitor utilization rates and predictors of use in a population of patients with or without type 2 diabetes (T2D)., Methods: This was a retrospective, single-center, descriptive chart review study. Individuals 18 years of age or older with HF were eligible for inclusion. Charts were reviewed between August 2021 and February 2022. The primary objective was to identify rates of SGLT2 inhibitor prescribing for patients with HF within a large academic medical center. Logistic regression analyses were conducted to identify potential SGLT2 inhibitor utilization predictors (demographic characteristics, medical history, laboratory results, specialty provider visits, medication use, and medication coverage)., Results: A total of 800 patients with HF were included: 377 with HF with reduced ejection fraction (HFrEF), 88 with mildly reduced EF, and 335 with preserved EF. Key baseline characteristics were as follows: 43% female; 47% Hispanic; 42% with T2D; 49% with established atherosclerotic cardiovascular disease; and mean age, 65 years. SGLT2 inhibitor utilization was 6.5% overall. Key predictors of utilization were as follows: T2D (odds ratio [OR], 33.4; 95% CI, 8.01-139.55), HFrEF (OR, 2.8; 95% CI, 1.45-5.51), HF clinic visit (OR, 2.5; 95% CI, 1.40-4.60), visit with pharmacist with prescriptive authority (OR, 5.8; 95% CI, 3.14-10.88), and enrollment in the hospital patient assistance program (OR, 2.3; 95% CI, 1.08-4.97)., Conclusion: Despite guideline recommendations, SGLT2 inhibitors are underutilized in patients with HF with or without T2D., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objective: To describe healthcare resource utilization (HCRU) and costs, in patients with newly diagnosed heart failure (HF) according to ejection fraction (EF) in Spain., Methods: Retrospective cohort study that analyzed anonymized, integrated and computerised medical records in Spain. Patients with ≥ 1 new HF diagnosis between January 2013 and September 2019 were included and followed-up during a 4-year period. Rates per 100 person-years of HCRU and costs were estimated., Results: Nineteen thousand nine hundred sixty-one patients were included, of whom 43.5%, 26.3%, 5.1% and 25.1% had HF with reduced, preserved, mildly reduced and unknown EF, respectively. From year 1 to 4, HF rates of outpatient visits decreased from 1149.5 (95% CI 1140.8-1159.3) to 765.5 (95% CI 745.9-784.5) and hospitalizations from 61.7 (95% CI 60.9-62.7) to 15.7(14.7-16.7) per 100 person-years. The majority of HF-related healthcare resource costs per patient were due to hospitalizations (year 1-4: 63.3-38.2%), followed by indirect costs (year 1-4: 12.2-29.0%), pharmacy (year 1-4: 11.9-19.9%), and outpatient care (year 1-4: 12.6-12.9%). Mean (SD) per patient HF-related costs decreased from 2509.6 (3518.5) to 1234.6 (1534.1) Euros (50% cost reduction). At baseline, 70.1% were taking beta-blockers, 56.3% renin-angiotensin system inhibitors, 11.8% mineralocorticoid receptor antagonists and 8.9% SGLT2 inhibitors. At 12 months, these numbers were 72.3%, 65.4%, 18.9% and 9.8%, respectively., Conclusions: Although the economic burden of HF decreased over time since diagnosis, it is still substantial. This reduction could be partially related to a survival bias (sick patients died early), but also to a better HF management. Despite that, there is still much room for improvement., (© 2023. The Author(s).)

Despite the growing body of evidence regarding the beneficial cardiovascular effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors, clinical data in individuals without diabetes, heart failure (HF), and/or chronic kidney disease (CKD) is limited. A systematic review of the literature was conducted in PubMed, Scopus, Web of Science, Cochrane Library, and Google Scholar, from database inception until May 4, 2023, to explore new evidence of SGLT2 inhibitors' cardiovascular benefits in individuals without diabetes, HF, and/or CKD. A total of 1156 individuals from 14 studies (13 randomized controlled trials and 1 nonrandomized study) were included. The results showed the benefits of SGLT2 inhibitors on blood pressure, weight, and body mass index in this population with an acceptable safety profile. The current evidence supports the potential role of SGLT2 inhibitors as primary prevention in individuals without diabetes, HF, and/or CKD. This review may shed light on the use of SGLT2 inhibitors in conditions such as stage A HF and metabolic syndrome. The literature trend is going toward uncovering SGLT2 inhibitors' role in stage B HF, different types of myocardial infarction, and cardiac arrhythmias., (© 2023, The American College of Clinical Pharmacology.)

Background: Sodium-glucose cotransporter-2 (SGLT2) inhibitors are guideline recommended in the management of heart failure (HF). Although these therapies can be initiated even in patients with comorbid chronic kidney disease, some patients may face deterioration of kidney function over time., Objectives: In this study, the authors sought to examine the safety and efficacy of continuing SGLT2 inhibitors in HF when the estimated glomerular filtration rate (eGFR) falls below thresholds for initiation., Methods: Associations between a deterioration of eGFR to <25 mL/min/1.73 m 2 , efficacy, and safety outcomes and treatment with dapagliflozin were evaluated in time-updated Cox proportional hazard models in a participant-level pooled analysis of the DAPA-HF (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure) and DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trials., Results: Among 11,007 patients, 347 (3.2%) experienced a deterioration of eGFR to <25 mL/min/1.73 m 2 at least once in follow-up. These patients had a higher risk of the primary composite outcome (HR: 1.87; 95% CI: 1.48-2.35; P < 0.001). The risk of the primary outcome was lower with dapagliflozin compared with placebo among patients who did (HR: 0.53; 95% CI: 0.33-0.83) as well as did not (HR: 0.78; 95% CI: 0.72-0.86) experience deterioration of eGFR to <25 mL/min/1.73 m 2 (P interaction  = 0.17). The risk of safety outcomes, including drug discontinuation, was higher among patients with deterioration of eGFR to <25 mL/min/1.73 m 2 ; however, rates remained similar between treatment groups including among those who remained on study drug., Conclusions: Patients with deterioration of eGFR to <25 mL/min/1.73 m 2 had elevated risks of cardiovascular outcomes yet appeared to benefit from continuation of dapagliflozin with no excess in safety outcomes between treatment groups. The benefit-to-risk ratio may favor continuation of dapagliflozin treatment in patients with HF experiencing deterioration of kidney function. Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure [DAPA-HF]; NCT03036124; and Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding Support and Author Disclosures DAPA-HF and DELIVER were funded by AstraZeneca. Dr Chatur is supported by the Canadian Arthur J.E. Child’s Cardiology Fellowship. Dr Vaduganathan has received research grant support, has served on advisory boards, or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has been a consultant for Amgen, AO Biome, Biogen, Boehringer Ingelheim, Corvia, Gilead, Myokardia, Cardurion, and Novartis. Dr Mc Causland has received research funding from NIDDK, Satellite Healthcare, Fifth Eye, Novartis, and Lexicon paid directly to his institution; and has received consulting fees from GS, and Zydus Therapeutics. Dr Desai has received research grant support from AstraZeneca, Alnylam, and Novartis; and has received consulting fees and/or honoraria from Abbott, AstraZeneca, Alnylam, Boehringer Ingelheim, Boston Scientific, Biofourmis, Corvidia, DalCor Pharma, Novartis, Relypsa, and Regeneron. Dr Jhund has received consulting fees, advisory board fees, and lecture fees from Novartis; has received advisory board fees from Cytokinetics; and has received grant support from Boehringer Ingelheim. Dr de Boer has received research grants and fees (to the institution, outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Novo Nordisk, and Roche; and has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside the submitted work). Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Novo Nordisk, Somologic, and Verily; and has served as a consultant to or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, GlaxoSmithKline, Intercept, Merck, Novartis, Novo Nordisk, and Prolaio. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim/Lilly, Novo Nordisk, Merck, Pfizer, and Bayer; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod receives consulting fees from Alnylam Pharmaceuticals, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eli Lilly, Esperion Therapeutics, Janssen Global Services, Lexicon Pharmaceuticals, Merck, Novo Nordisk, Pharmacosmos, Sanofi, Vifor Pharma; and receives grant/contract or travel fees from AstraZeneca and Boehringer Ingelheim. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma, Us2.ai, Janssen Research and Development, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group, Roche Diagnostics, Sanofi, and WebMD Global; and serves as the cofounder and nonexecutive director of Us2.ai. Dr Martinez receives consulting fees from AstraZeneca. Dr Shah is supported by research grants from the National Institutes of Health (U54 HL160273, R01 HL140731, R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GSK, Intellia, Ionis, Ironwood, Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Dr Sabatine has received research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, AstraZeneca, Boehringer-Ingelheim, Daiichi-Sankyo, Eisai, Intarcia, Ionis, Merck, Novartis, and Pfizer, as well as consulting fees from Amgen, Anthos Therapeutics, AstraZeneca, Beren Therapeutics, Boehringer Ingelheim, Dr Reddy’s Laboratories, Fibrogen, Intarcia, Merck, Moderna, Novo Nordisk, Precision Biosciences, and Silence Therapeutics; and is a member of the TIMI Study Group, which has also received institutional research grant support through Brigham and Women’s Hospital from ARCA Biopharma, Janssen Research and Development, Pfizer, Regeneron Pharmaceuticals, Roche, Siemens Healthcare Diagnostics, Softcell Medical, and Zora Biosciences. Dr Kober has received lecture fees from Novartis and Bristol Myers Squibb. Dr Ponikowski has received consulting fees, fees for serving on a Speakers Bureau, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cibiem, Novartis, and RenalGuard; has received lecture fees from Pfizer; has received fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Amgen; has received grant support (paid to his institution), fees for serving on a Speakers Bureau, consulting fees, and fees (paid to himself and to his institution) for serving as an investigator and steering or executive committee member for clinical trials from Vifor Pharma; has received fees for serving on a Speakers Bureau and consulting fees from Servier and Respicardia; and has received fees for serving on a Speakers Bureau from Berlin-Chemie. Dr Merkely has received personal fees from AstraZeneca and Servier. Dr Petersson is an employee and shareholder of AstraZeneca. Dr Langkilde is an employee and shareholder of AstraZeneca. Dr McMurray and his institution have received grants from AstraZeneca, Theracos, and GlaxoSmithKline during the conduct of the study and from Novartis, Amgen, Bristol Myers Squibb, Bayer, Abbvie, Dal-Cor, Kidney Research UK, and Cardurion; and has received grants from the British Heart Foundation. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, BMS, Celladon, Cytokinetics, Eidos, Gilead, GSK, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/National Heart, Lung, and Blood Institute, Neurotronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, Theracos, Us2.ai; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boeringer Ingelheim, BMS, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GSK, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, Akros, and Puretech Health., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Type 2 Diabetes Mellitus (T2DM) is a pandemic that affects millions of patients worldwide. Diabetes affects multiple organ systems leading to comorbidities including hypertension. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) recently have been approved for the treatment of T2DM and heart failure with reduced and preserved ejection fraction. Retrospective analyses of clinical trials have noted SGLT2 inhibitors to have a promising effect on blood pressure. Moreover, the observed blood pressure reduction is not just an acute effect of treatment initiation but has been shown to have a long-term impact on both systolic and diastolic blood pressure. The mechanism of action leading to the blood pressure reduction is still unclear; however, proposed mechanisms are related to the natriuretic effect, modification of the renin-angiotensin-aldosterone system, and/or the reduction in the sympathetic nervous system, SGLT2i should be considered as second-line medication in those patients with diabetes or heart disease and concomitant hypertension. This article reviews the pharmacology, side effect profile, and clinical trials surrounding the use of SGLT2i for the treatment of hypertension., (Copyright © 2022. Published by Elsevier Inc.)

Background: Patients with heart failure (HF) have a high burden of multimorbidity, often necessitating numerous medications. There may be clinical concern about introducing another medication, especially among individuals with polypharmacy., Objectives: This study examined the efficacy and safety of addition of dapagliflozin according to the number of concomitant medications in HF with mildly reduced or preserved ejection fraction., Methods: In this post hoc analysis of the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial, 6,263 participants with symptomatic HF with left ventricular ejection fraction >40% were randomized to dapagliflozin or placebo. Baseline medication use (including vitamins and supplements) was collected. Efficacy and safety outcomes were assessed by medication use categories ("nonpolypharmacy": <5 medications; "polypharmacy": 5 to 9 medications; and "hyperpolypharmacy": ≥10 medications) and continuously. The primary outcome was worsening HF or cardiovascular death., Results: Overall, 3,795 (60.6%) patients met polypharmacy and 1,886 (30.1%) met hyperpolypharmacy criteria. Higher numbers of medications were strongly associated with higher comorbidity burden and increased rates of the primary outcome. Compared with placebo, dapagliflozin similarly reduced the risk of the primary outcome irrespective of polypharmacy status (nonpolypharmacy HR: 0.88 [95% CI: 0.58-1.34]; polypharmacy HR: 0.88 [95% CI: 0.75-1.03]; hyperpolypharmacy HR: 0.73 [95% CI: 0.60-0.88]; P interaction  = 0.30). Similarly, benefits with dapagliflozin were consistent across the spectrum of total medication use (P interaction  = 0.06). Although adverse events increased with higher number of medications, they were not more frequent with dapagliflozin, regardless of polypharmacy status., Conclusions: In the DELIVER trial, dapagliflozin safely reduced worsening HF or cardiovascular death across a broad range of baseline medication use, including among individuals with polypharmacy (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213)., Competing Interests: Funding support and author disclosures The DELIVER trial was funded by AstraZeneca. Dr Peikert has received a research grant from the German Research Foundation. Dr Goyal has received consulting fees from Sensorum Health. Dr Vaduganathan has received research grant support; has served on advisory boards or has had speaker engagements with American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Chiesi, Cytokinetics, Lexicon Pharmaceuticals, Merck, Novartis, Novo Nordisk, Pharmacosmos, Relypsa, Roche Diagnostics, Sanofi, and Tricog Health; and has participated on clinical trial committees for studies sponsored by AstraZeneca, Galmed, Novartis, Bayer AG, Occlutech, and Impulse Dynamics. Dr Claggett has received consulting fees from Alnylam, Cardurion, Corvia, Cytokinetics, and Intellia, Rocket. Dr Vardeny has received institutional research support from AstraZeneca, Bayer, and Cardurion; and has served as a consultant or advisory board member for AstraZeneca, Cardior, Cytokinetics, and Sanofi-Pasteur. Dr Kosiborod has received research grant support from AstraZeneca, Boehringer Ingelheim, and Pfizer; has served as a consultant or on an advisory board for 35 Pharma, Alnylam, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Dexcom, Eli Lilly, Esperion Therapeutics, Imbria Pharmaceuticals, Janssen, Lexicon, Merck (Diabetes and Cardiovascular), Novo Nordisk, Pharmacosmos, Pfizer, scPharmaceuticals Structure Therapeutics, Vifor Pharma, and Youngene Therapeutics; has received other research support from AstraZeneca; and has received honoraria from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Desai has received institutional research grants from Abbott, AstraZeneca, Alnylam, Bayer, Novartis, and Pfizer; and has received personal consulting fees from Abbott, AstraZeneca, Alnylam, Avidity, Axon Therapeutics, Bayer, Biofourmis, GlaxoSmithKline, Medpace, Merck, Novartis, Parexel, Regeneron, River2Renal, Veristat, Verily, and Zydus. Dr Jhund has received speaker fees from AstraZeneca, Novartis, Alkem Metabolics, ProAdWise Communications, Sun Pharmaceuticals; has received advisory board fees from AstraZeneca, Boehringer Ingelheim, Novartis; has received research funding from AstraZeneca, Boehringer Ingelheim, Analog Devices Inc; and personal fees from Roche and Intas Pharma; has served as Director of Global Clinical Trial Partners (GCTP); and his employer, the University of Glasgow, has been remunerated for clinical trial work from AstraZeneca, Bayer AG, Novartis, and NovoNordisk. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and has served as cofounder and nonexecutive director of Us2.ai. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Martinez has received personal fees from AstraZeneca. Dr de Boer has received research grants and/or fees from AstraZeneca, Abbott, Boehringer Ingelheim, Cardior Pharmaceuticals GmbH, Ionis Pharmaceuticals Inc, Novo Nordisk, and Roche; and has had speaker engagements with Abbott, AstraZeneca, Bayer, Bristol Myers Squibb, Novartis, and Roche. Dr Hernandez has received research grants from American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Somologic and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Eidos, Intercept, Merck, and Novartis. Dr Shah has received research grants from the National Institutes of Health (U54 HL160273, R01 HL107577, R01 HL127028, R01 HL140731, and R01 HL149423), Actelion, AstraZeneca, Corvia, Novartis, and Pfizer; and has received consulting fees from Abbott, Actelion, AstraZeneca, Amgen, Aria CV, Axon Therapies, Bayer, Boehringer-Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardiora, Coridea, CVRx, Cyclerion, Cytokinetics, Edwards Lifesciences, Eidos, Eisai, Imara, Impulse Dynamics, GlaxoSmithKline, Intellia, Ionis, Ironwood, Eli Lilly, Merck, MyoKardia, Novartis, Novo Nordisk, Pfizer, Prothena, Regeneron, Rivus, Sanofi, Sardocor, Shifamed, Tenax, Tenaya, and United Therapeutics. Drs Petersson and Langkilde are employees and shareholders of AstraZeneca. Dr McMurray has received payments through Glasgow University from work on clinical trials, consulting and other activities from Amgen, AstraZeneca, Bayer, Cardurion, Cytokinetics, GSK, KBP Biosciences, and Novartis; personal consultancy fees from Alnylam Pharma, Bayer, BMS, George Clinical PTY Ltd, Ionis Pharma, Novartis, Regeneron Pharma, River 2 Renal Corporation; personal lecture fees from Abbott, Alkem Metabolics, AstraZeneca, Blue Ocean Scientific Solutions Ltd, Boehringer Ingelheim, Canadian Medical and Surgical Knowledge, Emcure Pharma Ltd, Eris Lifesciences, European Academy of CME, Hikma Pharmaceuticals, Imagica Health, Intas Pharma, J.B. Chemicals & Pharma Ltd, Lupin Pharma, Medscape/Heart.Org, ProAdWise Communications, Radcliffe Cardiology, Sun Pharma, The Corpus, Translation Research Group, Translational Medicine Academy; and he is a director of Global Clinical Trial Partners Ltd. Dr Solomon has received research grants (paid to institution) from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Eli Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Eli Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, Sarepta, Lexicon, Anacardio, and Valo. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023. Published by Elsevier Inc.)

Results from DELIVER trial and publication of EMPEROR-Preserved with sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with heart failure (HF) with ejection fraction (EF) > 40% represent a significant step forward in the treatment of HF with preserved EF (HFpEF). However, detailed analysis and attenuation of effect at higher EF levels have sparked some doubts about whether empagliflozin is effective across the entire spectrum of EF. HFpEF is no longer considered as one disease entity, but has been reconceptualized as a heterogenous group of phenotypes with derangements in multiple organ systems, driven by comorbidities. This heterogeneity suggests that it should not be considered as a single group in terms of treatment goals or clinical approach. Future research at the higher range of EF should ideally tailor investigations for unequivocally preserved EF (> 50%), consider the dynamic nature of EF over time, and use low-variability imaging techniques such as CMR. Furthermore, classifications based on pathophysiology and HF phenotypes beyond the EF construct will shape the design of future trials and help narrow down groups of patients who may respond to personalized treatment., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Not much is known about the effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) on echocardiographic parameters of left ventricular (LV) systolic function in patients with heart failure and reduced ejection fraction (HFrEF).We prospectively included 59 outpatients with HFrEF: 41 patients received SGLT2i with OMT (SGLT2i+ group), whereas eighteen patients received OMT without SGLT2i (SGLT2i- group). Myocardial work index (MWI), 3D ejection fraction (3D LVEF), and global longitudinal strain (GLS) were measured at baseline and after 3 months following treatment. At 3-month follow-up, the SGLT2i+ group showed significantly greater improvement in MWI than the SGLT2i- group. In both groups, there was a significant improvement in 3D LVEF and LV GLS, circulating NT-proBNP levels, and NYHA functional class, with significantly greater improvement in the SGLT2i+ group.In conclusion, the addition of SGLT2i to fully optimized background medical therapy resulted in a greater improvement of LV systolic function among outpatients with HFrEF., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)