Body mass index and cardiorenal outcomes in the EMPEROR-Preserved trial: Principal findings and meta-analysis with the DELIVER trial.

AIMS: Both low and high body mass index (BMI) are associated with poor heart failure outcomes. Whether BMI modifies benefits of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in heart failure with preserved ejection fraction (HFpEF) requires further investigation. METHODS AND RESULTS: Using EMPEROR-Preserved data, the effects of empagliflozin versus placebo on the risks for the primary outcome (hospitalization for heart failure [HHF] or cardiovascular [CV] death), change in estimated glomerular filtration rate (eGFR) slopes, change in Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), and secondary outcomes across baseline BMI categories (<25 kg/m2, 25 to <30 kg/m2, 30 to <35 kg/m2, 35 to <40 kg/m2 and ≥40 kg/m2) were examined, and a meta-analysis conducted with DELIVER. Forty-five percent had a BMI of ≥30 kg/m2. For the primary outcome, there was a consistent treatment effect of empagliflozin versus placebo across the BMI categories with no formal interaction (p trend = 0.19) by BMI categories. There was also no difference in the effects on secondary outcomes including total HHF (p trend = 0.19), CV death (p trend = 0.20), or eGFR slope with slower declines with empagliflozin regardless of BMI (range 1.12-1.71 ml/min/1.73 m2 relative to placebo, p trend = 0.85 for interaction), though there was no overall impact on the composite renal endpoint. The difference in weight change between empagliflozin and placebo was -0.59, -1.48, -1.54, -0.87, and - 2.67 kg in the lowest to highest BMI categories (p trend = 0.016 for interaction). A meta-analysis of data from EMPEROR-Preserved and DELIVER showed a consistent effect of SGLT2i versus placebo across BMI categories for the outcome of HHF or CV death. There was a trend toward greater absolute KCCQ-CSS benefit at 32 weeks with empagliflozin at higher BMIs (p = 0.08). CONCLUSIONS: Empagliflozin treatment resulted in broadly consistent cardiac effects across the range of BMI in patients with HFpEF. SGLT2i treatment yields benefit in patients with HFpEF regardless of baseline BMI.

Predictors of heart failure readmission and all-cause mortality in patients with acute heart failure.

BACKGROUND: Predischarge risk stratification of patients with acute heart failure (AHF) could facilitate tailored treatment and follow-up, however, simple scores to predict short-term risk for HF readmission or death are lacking. METHODS: We sought to develop a congestion-focused risk score using data from a prospective, two-center observational study in adults hospitalized for AHF. Laboratory data were collected on admission. Patients underwent physical examination, 4-zone, and in a subset 8-zone, lung ultrasound (LUS), and echocardiography at baseline. A second LUS was performed before discharge in a subset of patients. The primary endpoint was the composite of HF hospitalization or all-cause death. RESULTS: Among 350 patients (median age 75 years, 43% women), 88 participants (25%) were hospitalized or died within 90 days after discharge. A stepwise Cox regression model selected four significant independent predictors of the composite outcome, and each was assigned points proportional to its regression coefficient: NT-proBNP ≥2000 pg/mL (admission) (3 points), systolic blood pressure < 120 mmHg (baseline) (2 points), left atrial volume index ≥60 mL/m2 (baseline) (1 point) and ≥ 9 B-lines on predischarge 4-zone LUS (3 points). This risk score provided adequate risk discrimination for the composite outcome (HR 1.48 per 1 point increase, 95% confidence interval: 1.32-1.67, p < 0.001, C-statistic: 0.70). In a subset of patients with 8-zone LUS data (n = 176), results were similar (C-statistic: 0.72). CONCLUSIONS: A four-variable risk score integrating clinical, laboratory and ultrasound data may provide a simple approach for risk discrimination for 90-day adverse outcomes in patients with AHF if validated in future investigations.

Brief Report: Risk of Recurrent Interstitial Lung Disease From Osimertinib Versus Erlotinib Rechallenge After Symptomatic Osimertinib-Induced Interstitial Lung Disease.

Introduction: Interstitial lung disease (ILD) is the most frequent cause of drug-related mortality from EGFR tyrosine kinase inhibitors (TKIs). Yet, for patients with symptomatic osimertinib-induced ILD, the risk of recurrent ILD associated with EGFR TKI rechallenge, either with osimertinib or another TKI, such as erlotinib, is unclear. Methods: Retrospective study of 913 patients who received osimertinib treatment for EGFR mutation-positive NSCLC. Clinical characteristics, ILD treatment history, and subsequent anticancer therapy of patients with symptomatic osimertinib-induced ILD were collated. The primary end point was to compare the incidence of recurrent ILD with osimertinib versus erlotinib rechallenge. Results: Of 913 patients, 35 (3.8%) had symptomatic osimertinib-induced ILD, of which 12 (34%), 15 (43%), and eight (23%) had grade 2, 3 to 4, and 5 ILD, respectively. On ILD recovery, 17 patients had EGFR TKI rechallenge with eight received osimertinib and nine received erlotinib. The risk of recurrent ILD was higher with osimertinib rechallenge than erlotinib (p = 0.0498). Of eight, five (63%) developed recurrent ILD on osimertinib rechallenge, including three patients with fatal outcomes. In contrast, only one of nine patients (11%) treated with erlotinib had recurrent ILD. Median time to second ILD occurrence was 4.7 (range 0.7-12) weeks. Median time-to-treatment failure of patients with erlotinib rechallenge was 13.2 months (95% confidence interval: 8.6-15.0). Conclusions: The risk of recurrent ILD was considerably higher with osimertinib rechallenge than erlotinib. Osimertinib rechallenge should be avoided, whereas erlotinib may be considered in patients with symptomatic osimertinib-induced ILD.

Philadelphia Beverage Tax's Impact on Beverage Ad Expenditures and Number of Ads Purchased.

INTRODUCTION: On January 1, 2017, Philadelphia implemented a beverage excise tax. The study's objective was to determine whether beverage advertising expenditures and the number of beverage ads purchased changed in Philadelphia compared to Baltimore because of this tax. METHODS: Monthly beverage ad expenditures and the number of beverage ads purchased by brand from January 2016 through December 2019 were obtained. Ads were coded as being for taxed or not taxed beverages and analyzed in 2023. The primary outcomes were quarterly taxed beverage ad expenditures and number of ads purchased. A controlled interrupted time series design on segmented linear regression models was used. Models (aggregated and stratified by internet, spot TV, and local radio) compared whether levels and trends in the outcomes changed from pre- to post-tax in Philadelphia compared to Baltimore. RESULTS: There were no significant differences in taxed beverage advertising expenditures between Philadelphia and Baltimore for trends pretax, at implementation, or post-tax. There were 0.13 (95% CI: -0.25, -0.003) fewer quarterly taxed beverage ads purchased per 100 households in Philadelphia versus Baltimore at baseline. Among internet advertising, there were 0.42 (95% CI: -0.77, -0.06) fewer quarterly taxed beverage ads purchased per 100 households in Philadelphia versus Baltimore immediately post-tax. For spot TV ads, the percentage of taxed beverages ads purchased per quarter was greater at baseline in Philadelphia by 28.0 percentage points (95% CI: 1.9, 54.1). CONCLUSIONS: This study found little evidence of changes in mass media advertising on the examined platforms between 2016 and 2019 due to the Philadelphia beverage tax.

Advances in Multi-Modality Imaging in Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by abnormal growth of the myocardium with myofilament disarray and myocardial hyper-contractility, leading to left ventricular hypertrophy and fibrosis. Where culprit genes are identified, they typically relate to cardiomyocyte sarcomere structure and function. Multi-modality imaging plays a crucial role in the diagnosis, monitoring, and risk stratification of HCM, as well as in screening those at risk. Following the recent publication of the first European Society of Cardiology (ESC) cardiomyopathy guidelines, we build on previous reviews and explore the roles of electrocardiography, echocardiography, cardiac magnetic resonance (CMR), cardiac computed tomography (CT), and nuclear imaging. We examine each modality's strengths along with their limitations in turn, and discuss how they can be used in isolation, or in combination, to facilitate a personalized approach to patient care, as well as providing key information and robust safety and efficacy evidence within new areas of research.

Cost-effectiveness of Improved WIC Food Package for Preventing Childhood Obesity.

BACKGROUND AND OBJECTIVES: The Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) prevents food insecurity and supports nutrition for more than 3 million low-income young children. Our objectives were to determine the cost-effectiveness of changes to WIC's nutrition standards in 2009 for preventing obesity and to estimate impacts on socioeconomic and racial/ethnic inequities. METHODS: We conducted a cost-effectiveness analysis to estimate impacts from 2010 through 2019 of the 2009 WIC food package change on obesity risk for children aged 2 to 4 years participating in WIC. Microsimulation models estimated the cases of obesity prevented in 2019 and costs per quality-adjusted-life year gained. RESULTS: An estimated 14.0 million 2- to 4-year old US children (95% uncertainty interval (UI), 13.7-14.2 million) were reached by the updated WIC nutrition standards from 2010 through 2019. In 2019, an estimated 62 700 (95% UI, 53 900-71 100) cases of childhood obesity were prevented, entirely among children from households with low incomes, leading to improved health equity. The update was estimated to cost $10 600 per quality-adjusted-life year gained (95% UI, $9760-$11 700). If WIC had reached all eligible children, more than twice as many cases of childhood obesity would have been prevented. CONCLUSIONS: Updates to WIC's nutrition standards for young children in 2009 were estimated to be highly cost-effective for preventing childhood obesity and contributed to reducing socioeconomic and racial/ethnic inequities in obesity prevalence. Improving nutrition policies for young children can be a sound public health investment; future research should explore how to improve access to them.

Advertising and Stocking at Small Retailers: A Sweetened Beverage Excise Tax in Philadelphia.

INTRODUCTION: In 2017, Philadelphia enacted a $0.015 per ounce excise tax on SBs that covered both sugar-sweetened beverages and artificially-sweetened beverages, which reduced purchasing and consumption. This study assessed whether the tax also changed beverage advertising or stocking practices that could influence consumer behavior among stores in Philadelphia, Baltimore, and Philadelphia-adjacent counties not subject to the tax. METHODS: Using a longitudinal difference-in-differences approach, beverage advertising and availability changes were evaluated from 4-month pretax to 6-, 12-, and 24-month post-implementation in small independent stores in Philadelphia (n=34) and Philadelphia-adjacent counties (n=38) versus Baltimore (n=43), a demographically similar city without a tax. Mixed effects models tested whether beverage advertising/availability increased in Philadelphia and surrounding counties after implementation versus Baltimore, included store-level random intercepts, and were stratified by beverage tax status, type, size, and store ZIP code income. Data were collected from 2016 to 2018, and analyses were performed in 2022-2023. RESULTS: SB advertising increased post-tax in Philadelphia (6 months= +1.04 advertisements/store [95% CI=0.27, 1.80]; 12 months= +1.54 [95% CI=0.57, 2.52]; 24 months= +0.91 [95% CI=0.09, 1.72]) relative to Baltimore. This was driven by increased advertising of sweetened beverages in low-income ZIP codes. Marketing of SBs increased significantly in Philadelphia-adjacent counties relative to Baltimore. Although SB availability in Philadelphia did not change, it increased in surrounding county stores (6 months= +0.20 [95% CI=0.15, 0.25]; 12 months= +0.08 [95% CI=0.03, 0.12]) relative to Baltimore. CONCLUSIONS: Marketing of SBs, especially in low-income neighborhoods and in surrounding counties, increased following Philadelphia's beverage tax among small, independent retailers. These increases in advertising might have dampened the tax's effect on purchasing behaviors, although estimated effects on sales remained large.

Daily Saturated Fat and Sodium Content of Elementary School Meals in a Large Sample of 128 Geographically Diverse School Systems in the United States.

BACKGROUND: Despite federal regulations limiting saturated fat and sodium levels on a weekly average basis, daily nutrient content of school meals in the United States is not regulated, leading to potential large fluctuations and intake well in excess of dietary recommendations. OBJECTIVE: To assess the daily prevalence of potential public elementary school meal combinations that were high in saturated fat and sodium (using cutoffs based on the US Department of Agriculture weekly average reimbursable meal thresholds), and to identify saturated fat and sodium thresholds for entrées to limit full meals exceeding those cutoffs. DESIGN: Cross-sectional. PARTICIPANTS AND SETTING: Four weeks of publicly available public elementary school (kindergarten through grade five) breakfast and lunch menus with associated nutrition data were collected from a national stratified random sample of 128 school districts during fall 2019. MAIN OUTCOME MEASURES: Percent of meal combinations exceeding the saturated fat and Target 1 sodium thresholds were calculated, as well as thresholds for saturated fat and sodium levels in breakfast and lunch entrées. STATISTICAL ANALYSES: Descriptive statistics and logistic regression were used to examine the odds of alignment with sodium and saturated fat US Department of Agriculture thresholds. RESULTS: The prevalence of elementary breakfast and lunch meal combinations that were high in sodium was on average 11% and 12.4%, respectively, and for saturated fat was 10.6% and 34%, respectively. Entrées above certain thresholds (≥400 and ≥1,000 mg sodium and ≥4.5 and ≥6 g saturated fat for breakfast and lunch, respectively) had a higher odds of producing a reimbursable meal that was high in sodium and saturated fat. CONCLUSIONS: There is widespread availability of high-saturated fat and sodium elementary school meal combinations on a daily basis. Daily thresholds, in addition to weekly nutrient thresholds, as well as limits on sodium and saturated fat for entrées, may therefore be needed to prevent daily excess intake of saturated fat and sodium among elementary students.

Exercise Capacity in Patients With Obstructive Hypertrophic Cardiomyopathy: SEQUOIA-HCM Baseline Characteristics and Study Design.

Patients with obstructive hypertrophic cardiomyopathy (oHCM) have increased risk of arrhythmia, stroke, heart failure, and sudden death. Contemporary management of oHCM has decreased annual hospitalization and mortality rates, yet patients have worsening health-related quality of life due to impaired exercise capacity and persistent residual symptoms. Here we consider the design of clinical trials evaluating potential oHCM therapies in the context of SEQUOIA-HCM (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM). This large, phase 3 trial is now fully enrolled (N = 282). Baseline characteristics reflect an ethnically diverse population with characteristics typical of patients encountered clinically with substantial functional and symptom burden. The study will assess the effect of aficamten vs placebo, in addition to standard-of-care medications, on functional capacity and symptoms over 24 weeks. Future clinical trials could model the approach in SEQUOIA-HCM to evaluate the effect of potential therapies on the burden of oHCM. (Safety, Efficacy, and Quantitative Understanding of Obstruction Impact of Aficamten in HCM [SEQUOIA-HCM]; NCT05186818).

Effects of renin-angiotensin system blockers on outcomes from COVID-19: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Randomized controlled trials (RCTs) have assessed the effects of renin-angiotensin system (RAS) blockers in adults with coronavirus disease 2019 (COVID-19). This meta-analysis provides estimates of the safety and efficacy of treatment with (vs. without) RAS blockers from these trials. METHODS: PubMed, Web of Science, and ClinicalTrials.gov were searched (1 March-12 April 2023). Event/patient numbers were extracted, comparing angiotensin-converting enzyme (ACE) inhibitor/angiotensin-receptor blocker (ARB) treatment with no treatment, for the outcomes: intensive care unit (ICU) admission, mechanical ventilation, vasopressor use, acute kidney injury (AKI), renal replacement therapy (RRT), acute myocardial infarction, stroke/transient ischaemic attack, heart failure, thromboembolic events, and all-cause death. Fixed-effects meta-analysis estimates were pooled. RESULTS: Sixteen RCTs including 3492 patients were analysed. Compared with discontinuation of RAS blockers, continuation was not associated with increased risk of ICU [risk ratio (RR) 0.96, 0.66-1.41], ventilation (RR 0.77, 0.55-1.09), vasopressors (RR 0.92, 0.58-1.44), AKI (RR 1.01, 0.40-2.56), RRT (RR 1.01, 0.46-2.21), or thromboembolic events (RR 1.07, 0.36-3.19). RAS blocker initiation was not associated with increased risk of ICU (RR 0.71, 0.47-1.08), ventilation (RR 1.12, 0.91-1.38), AKI (RR 1.28, 0.89-1.86), RRT (RR 1.66, 0.89-3.12), or thromboembolic events (RR 1.20, 0.06-23.70), although vasopressor use increased (RR 1.27, 1.02-1.57). The RR for all-cause death in the continuation/discontinuation trials was 1.24 (0.80-1.92), and 1.22 (0.96-1.55) in the initiation trials. In patients with severe/critical COVID-19, RAS blocker initiation increased the risk of all-cause death (RR 1.31, 1.01-1.72). CONCLUSION: ACE inhibitors and ARBs may be continued in non-severe COVID-19 infection, where indicated. Conversely, initiation of RAS blockers may be harmful in critically ill patients.PROSPERO registration number: CRD42023408926.

A Sugar-Sweetened Beverage Excise Tax in California: Projected Benefits for Population Obesity and Health Equity.

INTRODUCTION: Amid the successes of local sugar-sweetened beverage (SSB) taxes, interest in state-wide policies has grown. This study evaluated the cost effectiveness of a hypothetical 2-cent-per-ounce excise tax in California and its implications for population health and health equity. METHODS: Using the Childhood Obesity Intervention Cost-Effectiveness Study microsimulation model, tax impacts on health, health equity, and cost effectiveness over 10 years in California were projected, both overall and stratified by race/ethnicity and income. Expanding on previous models, differences in the effect of intake of SSBs on weight by BMI category were incorporated. Costing was performed in 2020, and analyses were conducted in 2021-2022. RESULTS: The tax is projected to save $4.55 billion in healthcare costs, prevent 266,000 obesity cases in 2032, and gain 114,000 quality-adjusted life years. Cost-effectiveness metrics, including cost/quality-adjusted life year gained, were cost saving. Spending on SSBs was projected to decrease by $33 per adult and $26 per child overall in the first year. Reductions in obesity prevalence for Black and Hispanic Californians were 1.8 times larger than for White Californians, and reductions for adults with lowest incomes (<130% Federal Poverty Level) were 1.4 times the reduction among those with highest incomes (>350% Federal Poverty Level). The tax is projected to save $112 in obesity-related healthcare costs per $1 invested. CONCLUSIONS: A state-wide SSB tax in California would be cost saving, lead to reductions in obesity and improvement in SSB-related health equity, and lead to overall improvements in population health. The policy would generate more than $1.6 billion in state tax revenue annually that can also be used to improve health equity.

Appetite and its Regulation: Are there Palatable Interventions for Heart Failure?

PURPOSE OF REVIEW: Obesity is a major driver of heart failure (HF) incidence, and aggravates its pathophysiology. We summarized key reported and ongoing randomized clinical trials of appetite regulation and/or dietary energy restriction in individuals with HF. RECENT FINDINGS: Weight loss can be achieved by structured supervised diet programs with behavioural change, medications, or surgery. The new glucagon-like peptide-1 receptor agonists alone or in combination with other agents (e.g., glucose-dependent insulinotropic polypeptide and glucagon receptor agonists or amylin analogues) potently and sustainably reduce appetite, and, taken together with dietary advice, can produce substantial, life-changing, weight loss approaching that achieved by surgery. To date, data from the STEP-HFpEF trial show meaningful improvements in health status (Kansas City Cardiomyopathy Questionnaire). Effective weight management could relieve several drivers of HF, to complement the existing treatments for HF with both reduced and preserved ejection fraction. Further trials of weight loss interventions will provide more definitive evidence to understand their effects on clinical events in patients with HF.

A case report of myocardial infarction in a young transgender man with testosterone therapy: raising awareness on healthcare issues in the transgender community and a call for further research.

Background: People who are transgender may utilize masculinizing or feminizing gender-affirming hormonal therapy. Testosterone and oestrogen receptors are expressed throughout the cardiovascular system, yet the effects of these therapies on cardiovascular risk and outcomes are largely unknown. We report the case of a young transgender man with no discernible cardiovascular risk factors presenting with an acute coronary syndrome. Case summary: A 31-year-old transgender man utilizing intramuscular testosterone masculinizing gender-affirming hormonal therapy presented with central chest pain radiating to the left arm. He had no past medical history of hypertension, dyslipidaemia, diabetes, or smoking. Electrocardiography demonstrated infero-septal ST depression, and high-sensitivity troponin-I was elevated and increased to 19 686 ng/L. He was diagnosed with a non-ST-segment elevation myocardial infarction. Inpatient coronary angiography confirmed a critical focal lesion in the mid right coronary artery, which was managed with two drug-eluting stents. Medical management (i.e. aspirin, ticagrelor, atorvastatin, ramipril, and bisoprolol) and surveillance of residual plaque disease evident in the long tubular left main stem, proximal left anterior descending, and proximal circumflex vessels was undertaken. The masculinizing gender-affirming hormonal therapy was continued. Discussion: Despite a greater awareness of the potential risk of increased cardiovascular disease in transgender people, the fundamental lack of data regarding cardiovascular outcomes in transgender people may be contributing to healthcare inequalities in this population. We must implement better training, awareness, and research into transgender cardiovascular health to facilitate equitable and evidence-based outcomes.

Differentiating Cardiac Troponin Levels During Cardiac Myosin Inhibition or Cardiac Myosin Activation Treatments: Drug Effect or the Canary in the Coal Mine?

PURPOSE OF REVIEW: Cardiac myosin inhibitors (CMIs) and activators are emerging therapies for hypertrophic cardiomyopathy (HCM) and heart failure with reduced ejection fraction (HFrEF), respectively. However, their effects on cardiac troponin levels, a biomarker of myocardial injury, are incompletely understood. RECENT FINDINGS: In patients with HCM, CMIs cause substantial reductions in cardiac troponin levels which are reversible after stopping treatment. In patients with HFrEF, cardiac myosin activator (omecamtiv mecarbil) therapy cause modest increases in cardiac troponin levels which are reversible following treatment cessation and not associated with myocardial ischaemia or infarction. Transient changes in cardiac troponin levels might reflect alterations in cardiac contractility and mechanical stress. Such transient changes might not indicate cardiac injury and do not appear to be associated with adverse outcomes in the short to intermediate term. Longitudinal changes in troponin levels vary depending on the population and treatment. Further research is needed to elucidate mechanisms underlying changes in troponin levels.

Dietaryindex: A User-Friendly and Versatile R Package for Standardizing Dietary Pattern Analysis in Epidemiological and Clinical Studies.

Background: Few standardized and open-source tools exist for calculating dietary pattern indexes from dietary intake data in epidemiological and clinical studies. Miscalculations of dietary indexes, with suspected erroneous findings, are occasionally noted in the literature. Objective: The primary aim is to develop and validate dietaryindex, a user-friendly and versatile R package that standardizes the calculation of dietary indexes. Methods: Dietaryindex utilizes a two-step process: an initial calculation of serving size for each food and nutrient category, followed by the calculation of individual dietary indexes. It includes generic functions that accept any preprocessed serving sizes of food groups and nutrients, with the standard serving sizes defined according to the methodologies used in well-known prospective cohort studies. For ease of use, dietaryindex also offers one-step functions that directly reference common datasets and tools, including the National Health and Nutrition Examination Survey (NHANES) and Block Food Frequency Questionnaire, eliminating the need for data preprocessing. At least two independent researchers validated the serving size definitions and scoring algorithms of dietaryindex. Results: Dietaryindex can calculate multiple dietary indexes of high interest in research, including Healthy Eating Index (HEI) - 2020, Alternative Healthy Eating Index 2010, Dietary Approaches to Stop Hypertension Index, Alternate Mediterranean Diet Score, Dietary Inflammatory Index, American Cancer Society 2020 dietary index, and Planetary Health Diet Index from the EAT-Lancet Commission. In our validation process, dietaryindex demonstrated full accuracy (100%) in all generic functions with two-decimal rounding precision in comparison to hand-calculated results. Similarly, using NHANES 2017-2018 data and ASA24 and DHQ3 example data, the HEI2015 outputs from dietaryindex aligned (99.95%-100%) with results using the SAS codes from the National Cancer Institute. Conclusions: Dietaryindex is a user-friendly, versatile, and validated informatics tool for standardized dietary index calculations. We have open-sourced all the validation files and codes with detailed tutorials on GitHub (https://github.com/jamesjiadazhan/dietaryindex).

Dapagliflozin vs. metolazone in heart failure resistant to loop diuretics.

BACKGROUND AND AIMS: To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. METHODS AND RESULTS: A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. CONCLUSION: In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04860011.

A review of current key guidelines for managing high-risk patients with diabetes and heart failure and future prospects.

We reviewed recent guidelines on the management of heart failure (HF) in patients with diabetes. Major recommendations in European and US society guidelines were scrutinized. First, sodium-glucose co-transporter 2 inhibitors are now recommended treatments for all patients with symptomatic HF (stage C and D; New York Heart Association class II-IV), irrespective of the presence of type 2 diabetes and left ventricular ejection fraction (LVEF). Second, patients with HF and reduced EF (LVEF ≤40%) should have foundational therapies from four drug classes (sodium-glucose co-transporter 2 inhibitor, angiotensin-receptor neprilysin inhibitor, beta-blocker and mineralocorticoid receptor antagonist). Third, patients with HF with mildly reduced (41%-49%) and preserved (≥50%) LVEF may also benefit from angiotensin-receptor neprilysin inhibitor, beta-blocker and mineralocorticoid receptor antagonist therapy, although evidence for these is less robust. Fourth, selected patients should be considered for other therapies such as diuretics (if congestion), anticoagulation (if atrial fibrillation) and cardiac device therapy. Fifth, glucose-lowering therapies such as thiazolidinediones and certain dipeptidyl peptidase-4 inhibitors (such as saxagliptin and alogliptin) should be avoided in patients with HF. Sixth, guidelines recommend enrolment of patients with HF into exercise rehabilitation and multidisciplinary HF management programmes. Particular attention should be paid to important comorbidities such as obesity, alongside pharmacological therapies. As diabetes and obesity are major risk factors for HF, earlier consideration of, and diagnosis of HF, followed by guideline-directed medical therapy can meaningfully improve patients' lives. Diabetes doctors would do well to understand the basics of such guidelines to help improve all aspects of HF diagnosis and care.