Effect of dapagliflozin in patients with diabetes and heart failure with mildly reduced or preserved ejection fraction according to background glucose-lowering therapy: A pre-specified analysis of the DELIVER trial.

AIMS: Type 2 diabetes (T2D) and heart failure (HF) frequently coexist, but whether clinical outcomes and treatment effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) vary in relation to background glucose-lowering therapy (GLT) in this population is uncertain. METHODS AND RESULTS: DELIVER randomized patients with HF and left ventricular ejection fraction (LVEF) >40% to dapagliflozin or placebo. The primary outcome was a composite of worsening HF (HF hospitalization or urgent HF visit) or cardiovascular death. In this pre-specified analysis of participants with T2D, treatment effects were assessed by number and class of background GLT(s). Of 3150 participants with T2D at baseline, 22.9% were on no GLT, 36.5% were treated with 1 GLT, and 40.6% with ≥2 GLTs. During follow-up (median: 2.3 years), treatment benefits of dapagliflozin (vs. placebo) on the primary outcome were consistent irrespective of the number of background GLTs (0 GLTs: hazard ratio [HR] 0.71, 95% confidence interval [CI] 0.50-1.00; 1 GLT: HR 1.04, 95% CI 0.80-1.34; ≥2 GLTs: HR 0.71, 95% CI 0.56-0.90; pinteraction = 0.59). Similar findings were observed among participants with (HR 0.73, 95% CI 0.59-0.92) and without background metformin use (HR 0.89, 95% CI 0.72-1.11; pinteraction = 0.22) and in participants with (HR 0.89, 95% CI 0.69-1.16) and without background insulin use (HR 0.78, 95% CI 0.65-0.95; pinteraction = 0.45). Dapagliflozin was well-tolerated irrespective of the number of background GLTs. CONCLUSIONS: Dapagliflozin safely and consistently improved clinical outcomes among individuals with T2D and HF with LVEF >40% irrespective of the number and class of background GLTs, and the benefits were not influenced by concomitant metformin or insulin use. These data bolster contemporary guidelines supporting first-line SGLT2i among individuals with T2D and HF, irrespective of background GLT.

Dapagliflozin and quality of life measured using the EuroQol 5-dimension questionnaire in patients with heart failure with reduced and mildly reduced/preserved ejection fraction.

AIMS: Although much is known about the usefulness of heart failure (HF)-specific instruments for assessing patient well-being, less is known about the value of generic instruments for the measurement of health-related quality of life (HRQL) in HF. The aim of this study was to assess the relationship between the EuroQol 5-dimension 5-level (EQ-5D-5L) visual analogue scale (VAS) and index scores, clinical characteristics, and outcomes in patients with HF and the effect of dapagliflozin on these scores. METHODS AND RESULTS: We performed a patient-level pooled analysis of the DAPA-HF and DELIVER trials, which investigated the effectiveness and safety of dapagliflozin in patients with HF and reduced ejection fraction (HFrEF) and mildly reduced/preserved ejection fraction (HFmrEF/HFpEF), respectively. Patients reporting higher (better) EQ-5D-5L VAS and index scores had a lower prevalence of comorbidities, including atrial fibrillation and hypertension, than patients with a worse score. They were also more likely to have better investigator-reported (New York Heart Association class) and patient-self-reported (Kansas City Cardiomyopathy Questionnaire) health status and lower median N-terminal pro-B-type natriuretic peptide levels. Compared to patients with the lowest scores (Q1), those with higher EQ-5D-5L VAS scores had better outcomes: the hazard ratio for the composite of cardiovascular death or worsening HF was 0.81 (95% confidence interval 0.72-0.91) in Q2, 0.74 (0.65-0.84) in Q3, and 0.62 (0.54-0.72) in Q4. The risk of each component of the composite outcome, and all-cause death, was also lower in patients with better scores. Similar findings were observed for the index score. Treatment with dapagliflozin improved both EQ-5D-5L VAS and index scores across the range of ejection fraction. CONCLUSIONS: Both higher (better) EQ-5D-5L VAS and index scores were associated with better outcomes. Dapagliflozin treatment improved EQ-5D-5L VAS and index scores, irrespective of ejection fraction.

Dapagliflozin and Timing of Prior Heart Failure Hospitalization: A Patient-Level Meta-Analysis of DAPA-HF and DELIVER.

BACKGROUND: Patients recently hospitalized for heart failure (HF) are at a higher risk of adverse clinical outcomes, but they may experience a greater absolute and relative benefit from effective therapies than individuals who are considered more "stable." OBJECTIVES: The authors examined the effects of dapagliflozin according to the timing of prior HF hospitalization in a patient-level pooled analysis of 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). METHODS: A total of 11,007 patients were randomized in DAPA-HF and DELIVER. The primary outcome was the composite of worsening HF or cardiovascular death. RESULTS: In total, 12.4% were hospitalized for HF within 3 months of randomization, 14.2% between 3 and 12 months, and 16.8% more than 1 year before randomization, whereas 56.5% had not been hospitalized. The risk of the primary endpoint was inversely associated with time from prior HF hospitalization, and patients with a recent HF hospitalization had the highest risk. Compared with placebo, dapagliflozin reduced the risk of the primary outcome across HF hospitalization category (0-3 months, HR: 0.66 [95% CI: 0.55-0.81]; 3-12 months, HR: 0.73 [95% CI: 0.59-0.90]; >1 year, HR: 0.91 [95% CI: 0.74-1.12]; and no prior hospitalization, HR: 0.83 [95% CI: 0.73-0.94]; Pinteraction = 0.09). The number of patients needed to treat with dapagliflozin to prevent 1 event over the median follow-up of 22 months was 13, 20, 23, and 28, respectively. The beneficial effect was consistent across the range of LVEF regardless of HF hospitalization category. CONCLUSIONS: The relative benefits of dapagliflozin were consistent across the range of LVEF regardless of the timing of the most recent HF hospitalization with a greater absolute benefit in patients with recent hospitalization.

Sodium Glucose Co-transporter 2 Inhibitors and Major Adverse Cardiovascular Outcomes: A SMART-C Collaborative Meta-Analysis.

BACKGROUND: Sodium glucose co-transporter 2 inhibitors (SGLT2i) consistently improve heart failure and kidney-related outcomes; however, effects on major adverse cardiovascular events (MACE) across different patient populations are less clear. METHODS: This was a collaborative trial-level meta-analysis from the SGLT2i meta-analysis cardio-renal trialists consortium, which includes all phase 3, placebo-controlled, outcomes trials of SGLT2i across three patient populations (diabetes at high risk for atherosclerotic cardiovascular disease [ASCVD], heart failure [HF], or chronic kidney disease [CKD]). The outcomes of interest were MACE (composite of CV death, myocardial infarction [MI], or stroke), individual components of MACE (inclusive of fatal and non-fatal events), all-cause mortality, and death subtypes. Effect estimates for SGLT2i vs. placebo were meta-analyzed across trials and examined across key subgroups (established ASCVD, prior MI, diabetes, prior HF, albuminuria, CKD stages and risk groups). RESULTS: A total of 78,607 patients across 11 trials were included: 42,568 (54.2%), 20,725 (26.4%), and 15,314 (19.5%) were included from trials of patients with diabetes at high risk for ASCVD, HF, or CKD, respectively. SGLT2i reduced the rate of MACE by 9% (HR 0.91 [95% CI 0.87-0.96], p<0.0001) with a consistent effect across all three patient populations (I2=0%) and across all key subgroups. This effect was primarily driven by a reduction in CV death (HR 0.86 [0.81-0.92], p<0.0001), with no significant effect for MI in the overall population (HR 0.95 [0.87-1.04], p=0.29), and no effect on stroke (HR 0.99 [0.91-1.07], p=0.77). The benefit for CV death was driven primarily by reductions in HF death and sudden cardiac death (HR 0.68 [0.46-1.02] and HR 0.86 [0.78-0.95], respectively) and was generally consistent across subgroups, with the possible exception of being more apparent in those with albuminuria (Pint=0.02). CONCLUSIONS: SGLT2i reduce the risk of MACE across a broad range of patients irrespective of ASCVD, diabetes, kidney function or other major clinical characteristics at baseline. This effect is driven primarily by a reduction of CV death, particularly HF and sudden cardiac death, without a significant effect on MI in the overall population, and no effect on stroke. These data may help inform selection for SGLT2i therapies across the spectrum of cardiovascular-kidney-metabolic disease.

Secondary Prevention in Patients With Stroke Versus Myocardial Infarction: Analysis of 2 National Cohorts.

BACKGROUND: The implementation of preventive therapies among patients with stroke remains inadequately explored, especially when compared with patients with myocardial infarction (MI), despite sharing similar vascular risk profiles. We tested the hypothesis that participants with a history of stroke have a worse cardiovascular prevention profile in comparison to participants with MI. METHODS AND RESULTS: In cross-sectional analyses within the UK Biobank and All of Us Research Program, involving 14 760 (9193 strokes, 5567 MIs) and 7315 (2948 strokes, 4367 MIs) participants, respectively, we evaluated cardiovascular prevention profiles assessing low-density lipoprotein (<100 mg/dL), blood pressure (systolic, <140 mm Hg; and diastolic, <90 mm Hg), statin and antiplatelet use, and a cardiovascular prevention score that required meeting at least 3 of these criteria. The results revealed that, within the UK Biobank, patients with stroke had significantly lower odds of meeting all the preventive criteria compared with patients with MI: low-density lipoprotein control (odds ratio [OR], 0.73 [95% CI, 0.68-0.78]; P<0.001), blood pressure control (OR, 0.63 [95% CI, 0.59-0.68]; P<0.001), statin use (OR, 0.45 [95% CI, 0.42-0.48]; P<0.001), antiplatelet therapy use (OR, 0.30 [95% CI, 0.27-0.32]; P<0.001), and cardiovascular prevention score (OR, 0.42 [95% CI, 0.39-0.45]; P<0.001). Similar patterns were observed in the All of Us Research Program, with significant differences across all comparisons (P<0.05), and further analysis suggested that the odds of having a good cardiovascular prevention score were influenced by race and ethnicity as well as neighborhood deprivation levels (interaction P<0.05 in both cases). CONCLUSIONS: In 2 independent national cohorts, patients with stroke showed poorer cardiovascular prevention profiles and lower adherence to guideline-directed therapies compared with patients with MI. These findings underscore the need to explore the reasons behind the underuse of secondary prevention in vulnerable stroke survivors.

Use of Sodium-Glucose Cotransporter Inhibitors in Type 1 Diabetes: The Promise and the Perils.

OBJECTIVE: Despite improvements in glucose monitoring technologies, insulin formulations and insulin delivery systems, too many patients with type 1 diabetes (T1D) continue to struggle to meet their glycemic goals. As a result, they suffer from high rates of microvascular and macrovascular disease. Titration of insulin therapy, while essential to the care of these patients, is often limited by undesirable side effects of hypoglycemia and weight gain. Sodium-glucose cotransporter (SGLT) inhibitors have been proposed as a potential adjunctive therapy to insulin that may offset some of these effects, while simultaneously enabling patients with T1D to potentially reap the cardiovascular and renal benefits afforded by these agents in those with type 2 diabetes. This review summarizes and contextualizes the clinical trial data that has emerged with these agents in this specific population. METHODS: A clinical review based on current literature was generated by the authors. RESULTS: This review summarizes the data from several clinical trial programs investigating the use of SGLT inhibitors in T1D, describing the potential benefits and the ketosis-related adverse events of these agents (including euglycemic DKA), along with a discussion of possible mitigation strategies to reduce this risk. CONCLUSION: Although theoretically SGLT inhibitors have the potential to improve metabolic, cardiovascular, and renal outcomes in patients with T1D, the risks of diabetic ketoacidosis currently represent an important limitation to the widespread use of these agents. If treatment is undertaken, caution must be taken, with implementation of effective mitigation strategies being essential.

Dapagliflozin and Days of Full Health Lost in the DAPA-HF Trial.

BACKGROUND: Conventional time-to-first-event analyses cannot incorporate recurrent hospitalizations and patient well-being in a single outcome. OBJECTIVES: To overcome this limitation, we tested an integrated measure that includes days lost from death and hospitalization, and additional days of full health lost through diminished well-being. METHODS: The effect of dapagliflozin on this integrated measure was assessed in the DAPA-HF (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure) trial, which examined the efficacy of dapagliflozin, compared with placebo, in patients with NYHA functional class II to IV heart failure and a left ventricular ejection fraction ≤40%. RESULTS: Over 360 days, patients in the dapagliflozin group (n = 2,127) lost 10.6 ± 1.0 (2.9%) of potential follow-up days through cardiovascular death and heart failure hospitalization, compared with 14.4 ± 1.0 days (4.0%) in the placebo group (n = 2,108), and this component of all measures of days lost accounted for the greatest between-treatment difference (-3.8 days [95% CI: -6.6 to -1.0 days]). Patients receiving dapagliflozin also had fewer days lost to death and hospitalization from all causes vs placebo (15.5 ± 1.1 days [4.3%] vs 20.3 ± 1.1 days [5.6%]). When additional days of full health lost (ie, adjusted for Kansas City Cardiomyopathy Questionnaire-overall summary score) were added, total days lost were 110.6 ± 1.6 days (30.7%) with dapagliflozin vs 116.9 ± 1.6 days (32.5%) with placebo. The difference in all measures between the 2 groups increased over time (ie, days lost by death and hospitalization -0.9 days [-0.7%] at 120 days, -2.3 days [-1.0%] at 240 days, and -4.8 days [-1.3%] at 360 days). CONCLUSIONS: Dapagliflozin reduced the total days of potential full health lost due to death, hospitalizations, and impaired well-being, and this benefit increased over time during the first year. (Study to Evaluate the Effect of Dapagliflozin on the Incidence of Worsening Heart Failure or Cardiovascular Death in Patients With Chronic Heart Failure; NCT03036124).

Prognostic Models for Mortality and Morbidity in Heart Failure With Preserved Ejection Fraction.

Importance: Accurate risk prediction of morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF) may help clinicians risk stratify and inform care decisions. Objective: To develop and validate a novel prediction model for clinical outcomes in patients with HFpEF using routinely collected variables and to compare it with a biomarker-driven approach. Design, Setting, and Participants: Data were used from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial to derive the prediction model, and data from the Angiotensin Receptor Neprilysin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) and the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-PRESERVE) trials were used to validate it. The outcomes were the composite of HF hospitalization (HFH) or cardiovascular death, cardiovascular death, and all-cause death. A total of 30 baseline candidate variables were selected in a stepwise fashion using multivariable analyses to create the models. Data were analyzed from January 2023 to June 2023. Exposures: Models to estimate the 1-year and 2-year risk of cardiovascular death or hospitalization for heart failure, cardiovascular death, and all-cause death. Results: Data from 6263 individuals in the DELIVER trial were used to derive the prediction model and data from 4796 individuals in the PARAGON-HF trial and 4128 individuals in the I-PRESERVE trial were used to validate it. The final prediction model for the composite outcome included 11 variables: N-terminal pro-brain natriuretic peptide (NT-proBNP) level, HFH within the past 6 months, creatinine level, diabetes, geographic region, HF duration, treatment with a sodium-glucose cotransporter 2 inhibitor, chronic obstructive pulmonary disease, transient ischemic attack/stroke, any previous HFH, and heart rate. This model showed good discrimination (C statistic at 1 year, 0.73; 95% CI, 0.71-0.75) in both validation cohorts (C statistic at 1 year, 0.71; 95% CI, 0.69-0.74 in PARAGON-HF and 0.75; 95% CI, 0.73-0.78 in I-PRESERVE) and calibration. The model showed similar discrimination to a biomarker-driven model including high-sensitivity cardiac troponin T and significantly better discrimination than the Meta-Analysis Global Group in Chronic (MAGGIC) risk score (C statistic at 1 year, 0.60; 95% CI, 0.58-0.63; delta C statistic, 0.13; 95% CI, 0.10-0.15; P < .001) and NT-proBNP level alone (C statistic at 1 year, 0.66; 95% CI, 0.64-0.68; delta C statistic, 0.07; 95% CI, 0.05-0.08; P < .001). Models derived for the prediction of all-cause and cardiovascular death also performed well. An online calculator was created to allow calculation of an individual's risk. Conclusions and Relevance: In this prognostic study, a robust prediction model for clinical outcomes in HFpEF was developed and validated using routinely collected variables. The model performed better than NT-proBNP level alone. The model may help clinicians to identify high-risk patients and guide treatment decisions in HFpEF.

Dapagliflozin in patients with heart failure and previous myocardial infarction: A participant-level pooled analysis of DAPA-HF and DELIVER.

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; pinteraction = 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.

Cardiovascular Outcomes in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study).

BACKGROUND: Cardiovascular disease is a major cause of morbidity and mortality in patients with type 2 diabetes. The effects of glucose-lowering medications on cardiovascular outcomes in individuals with type 2 diabetes and low cardiovascular risk are unclear. We investigated cardiovascular outcomes by treatment group in participants randomly assigned to insulin glargine, glimepiride, liraglutide, or sitagliptin, added to baseline metformin, in GRADE (Glycemia Reduction Approaches in Type 2 Diabetes: A Comparative Effectiveness Study). METHODS: A total of 5047 participants with a mean±SD age of 57.2±10.0 years, type 2 diabetes duration of 4.0±2.7 years, and low baseline prevalence of cardiovascular disease (myocardial infarction, 5.1%; cerebrovascular accident, 2.0%) were followed for a median of 5 years. Prespecified outcomes included between-group time-to-first event analyses of MACE-3 (composite of major adverse cardiovascular events: cardiovascular death, myocardial infarction, and stroke), MACE-4 (MACE-3+unstable angina requiring hospitalization or revascularization), MACE-5 (MACE-4+coronary revascularization), MACE-6 (MACE-5+hospitalization for heart failure), and the individual components. MACE outcomes and hospitalization for heart failure in the liraglutide-treated group were compared with the other groups combined using Cox proportional hazards models. MACE-6 was also analyzed as recurrent events using a proportional rate model to compare all treatment groups. RESULTS: We observed no statistically significant differences in the cumulative incidence of first MACE-3, MACE-4, MACE-5, or MACE-6, or their individual components, by randomized treatment group. However, when compared with the other treatment groups combined, the liraglutide-treated group had a significantly lower risk of MACE-5 (adjusted hazard ratio, 0.70 [95% CI, 0.54-0.91]; P=0.021), MACE-6 (adjusted hazard ratio, 0.70 [95% CI, 0.55-0.90]; P=0.021), and hospitalization for heart failure (adjusted hazard ratio, 0.49 [95% CI, 0.28-0.86]; P=0.022). Compared with the liraglutide group, significantly higher rates of recurrent MACE-6 events occurred in the groups treated with glimepiride (rate ratio, 1.61 [95% CI, 1.13-2.29]) or sitagliptin (rate ratio 1.75; [95% CI, 1.24-2.48]). CONCLUSIONS: This comparative effectiveness study of a contemporary cohort of adults with type 2 diabetes, largely without established cardiovascular disease, suggests that liraglutide treatment may reduce the risk of cardiovascular events in patients at relatively low risk compared with other commonly used glucose-lowering medications. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01794143.

Insulin Requirement and Infrainguinal Bypass Outcomes in Patients with Peripheral Arterial Disease.

BACKGROUND: Diabetes mellitus (DM) is a major risk factor for peripheral artery disease. The association of DM with major adverse limb events (MALE) after lower extremity revascularization remains controversial, as patients with diabetes are typically analyzed as a single, homogenous group. Using a large national database, this study examines the impact of insulin use and glycemic control on the outcomes following infrainguinal bypass. The hypothesis is that prevalent insulin therapy and elevated hemoglobin A1c (HbA1c) are associated with an increased risk of MALEs after infrainguinal bypass in patients with DM and could therefore be used for risk stratification. METHODS: The Vascular Quality Initiative database files for infrainguinal bypass (2007-2021) were retrospectively reviewed. Patients with DM undergoing bypass for peripheral artery disease were included. Patients on dialysis or with prior kidney transplantation were excluded. The characteristics and outcomes of patients with insulin-requiring diabetes mellitus (IRDM) were compared to those of patients not requiring insulin (noninsulin-requiring diabetes mellitus [NIRDM]) prior to the bypass procedure. RESULTS: A total of 9,686 patients with DM (56% IRDM) underwent bypass. Patients with IRDM were significantly younger than patients with NIRDM, more likely to be female (P < 0.01), African American (P < 0.01), and Hispanic (P = 0.031), and more likely to have comorbidities and be categorized into American Society of Anesthesiologist classes IV-V. They were more likely to be treated for chronic limb-threatening ischemia (P < 0.001). Patients with IRDM had significantly higher perioperative complications with no difference in perioperative mortality between the 2 groups. Beyond the perioperative period, with a mean follow-up of 427 days, patients with IRDM had significantly lower crude rates of primary patency and higher crude rates of major amputation, MALE, and mortality compared to patients with NIRDM. Regression analyses demonstrated that insulin requirement, but not HbA1c, was independently associated with a higher risk of MALE (hazard ratio = 1.17 [1.06-1.29]) and mortality (hazard ratio = 1.28 [1.16-1.43]). CONCLUSIONS: Insulin requirement, but not HbA1c, is significantly associated with MALEs and survival after infrainguinal bypass in the Vascular Quality Initiative. Stratification of patients with DM based on their prevalent insulin use prior to infrainguinal bypass surgery could improve the prediction of outcomes of peripheral arterial bypass surgery in patients with diabetes.

How do SGLT2 inhibitors protect the kidney? A mediation analysis of the EMPA-REG OUTCOME trial.

INTRODUCTION: Mechanisms underlying kidney benefits with sodium-glucose cotransporter-2 (SGLT2) inhibition in heart failure and/or type 2 diabetes (T2D) with established cardiovascular disease are currently unclear. METHODS: We evaluated post hoc the factors mediating the effect of empagliflozin on a composite kidney outcome (first sustained estimate glomerular filtration rate ≥40% reduction from baseline, initiation of renal replacement therapy, or death due to kidney disease) in EMPA-REG OUTCOME. Variables, calculated as change from baseline or updated mean, were evaluated as time-dependent covariates and using a landmark approach (at Week 12) in Cox regression analyses. In multivariable analyses, variables with the greatest mediating effect were added using a step-up procedure. RESULTS: In univariable time-dependent updated mean covariate analyses, the strongest mediator was hematocrit (99.5% mediation). Hemoglobin, uric acid, and urine albumin-to-creatinine ratio mediated 79.4%, 33.2%, and 31.0%, respectively. Multivariable analyses were not performed due to the very strong mediation effect of hematocrit. In univariable Week 12 landmark change from baseline analyses, the strongest mediators included hematocrit (40.7%), glycated hemoglobin (28.3%), systolic blood pressure (16.8%), and free fatty acids (16.5%), which yielded a combined mediation of 78.9% in multivariable analysis. CONCLUSIONS: Changes in hematocrit and hemoglobin were the strongest mediators of empagliflozin's kidney benefits in EMPA-REG OUTCOME participants with T2D and cardiovascular disease.

Effects of Dapagliflozin in Patients in Asia: A Post Hoc Subgroup Analysis From the DELIVER Trial.

Background: Patients with heart failure (HF) with mildly reduced or preserved ejection fraction in Asia may have different clinical characteristics and outcomes compared with patients from other parts of the world. Objectives: The purpose of this study was to investigate the clinical characteristics, safety, and efficacy of dapagliflozin in patients in Asia vs outside Asia in the DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients with Preserved Ejection Fraction Heart Failure) trial. Methods: In the DELIVER trial, patients with HF and left ventricular ejection fraction >40% were enrolled across 353 sites in 20 countries. The effects of dapagliflozin vs placebo on primary (composite of worsening HF or cardiovascular death) and secondary outcomes were compared in patients from Asia vs outside Asia. Results: Among 6,263 participants, 1,226 (19.6%) were enrolled in Asia. Participants from Asia were less likely to have diabetes, hypertension, history of myocardial infarction, or obesity. After adjusting for clinically relevant characteristics, those in Asia had similar risks of primary composite outcome compared with those from outside Asia (HR: 0.97; 95% CI: 0.82-1.15). Those in Asia had a lower risk of all-cause mortality compared with those enrolled outside Asia (HR: 0.54; 95% CI: 0.44-0.66). Enrollment from Asia did not modify the effect of dapagliflozin on the primary outcome (Pinteraction = 0.54). Serious adverse events and rates of drug discontinuation were also balanced in both treatment arms, irrespective of enrollment in Asia vs outside Asia. Conclusions: In the global DELIVER trial, dapagliflozin reduced the risk of CV death or worsening HF events and was well tolerated among participants enrolled in both Asia and other geographic regions.

Dapagliflozin and Mode of Death in Heart Failure With Improved Ejection Fraction: A Post Hoc Analysis of the DELIVER Trial.

Importance: Heart failure with improved ejection fraction (HFimpEF), defined as prior left ventricular ejection fraction (LVEF) 40% or lower that has increased to greater than 40%, is understudied. Objective: To examine mode of death and the association of dapagliflozin with reductions in cause-specific death in patients with HFimpEF. Design, Setting, and Participants: This was a post hoc analysis from the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) randomized clinical trial, conducted from August 2018 to December 2020. The trial randomly assigned patients with HF with LVEF greater than 40%, New York Heart Association class II to IV symptoms, and elevated natriuretic peptides to treatment with dapagliflozin (10 mg, once daily) or placebo. The presence of HFimpEF was captured through study case report forms. The primary outcome was a composite of worsening HF events (hospitalization or urgent HF visits) or cardiovascular death. Clinical outcomes were adjudicated by a blinded clinical end points committee. Data were analyzed from May 2022 to August 2023. Intervention: Dapagliflozin vs placebo. Main Outcomes and Measures: The mode of death in relation to HFimpEF status was examined, as well as the association of randomized treatment with cause-specific death in Cox regression models. Results: Of 1151 patients with HFimpEF in DELIVER, 190 (16.5%) died, compared with 833 patients (16.3%) of 5112 with LVEF consistently greater than 40%. The overall distribution of mode of death was similar in those with HFimpEF compared with those with LVEF consistently greater than 40% (noncardiovascular death: 103 of 190 [54%] vs 428 of 833 [51%]; cardiovascular death: 87 of 190 [46%] vs 405 of 833 [49%], respectively). Most deaths in individuals with HFimpEF were noncardiovascular (103 of 180 [54%]). For cardiovascular deaths, sudden deaths were most common (36 of 190 events [19%]), followed by HF-related (29 of 190 events [15%]). Among patients with HFimpEF, treatment with dapagliflozin was associated with lower rates of cardiovascular death relative to placebo, a difference primarily due to lower rates of sudden death (hazard ratio, 0.38; 95% CI, 0.18-0.79; P for interaction = .01). Conclusions and Relevance: The findings in this study support current guideline recommendations for use of sodium-glucose transport protein 2 inhibitor therapy, and further suggest that the addition of a sodium-glucose transport protein 2 inhibitor therapy to other guideline-directed medical therapies may help reduce cardiovascular mortality in patients with HFimpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.

Contemporary Use and Implications of Beta-Blockers in Patients With HFmrEF or HFpEF: The DELIVER Trial.

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; Pinteraction = 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).

Empagliflozin in Heart Failure: Regional Nephron Sodium Handling Effects.

SIGNIFICANCE STATEMENT: The effect of sodium-glucose cotransporter-2 inhibitors (SGLT2i) on regional tubular sodium handling is poorly understood in humans. In this study, empagliflozin substantially decreased lithium reabsorption in the proximal tubule (PT) (a marker of proximal tubular sodium reabsorption), a magnitude out of proportion to that expected with only inhibition of sodium-glucose cotransporter-2. This finding was not driven by an "osmotic diuretic" effect; however, several parameters changed in a manner consistent with inhibition of the sodium-hydrogen exchanger 3. The large changes in proximal tubular handling were acutely buffered by increased reabsorption in both the loop of Henle and the distal nephron, resulting in the observed modest acute natriuresis with these agents. After 14 days of empagliflozin, natriuresis waned due to increased reabsorption in the PT and/or loop of Henle. These findings confirm in humans that SGLT2i have complex and important effects on renal tubular solute handling. BACKGROUND: The effect of SGLT2i on regional tubular sodium handling is poorly understood in humans but may be important for the cardiorenal benefits. METHODS: This study used a previously reported randomized, placebo-controlled crossover study of empagliflozin 10 mg daily in patients with diabetes and heart failure. Sodium handling in the PT, loop of Henle (loop), and distal nephron was assessed at baseline and day 14 using fractional excretion of lithium (FELi), capturing PT/loop sodium reabsorption. Assessments were made with and without antagonism of sodium reabsorption through the loop using bumetanide. RESULTS: Empagliflozin resulted in a large decrease in sodium reabsorption in the PT (increase in FELi=7.5%±10.6%, P = 0.001), with several observations suggesting inhibition of PT sodium hydrogen exchanger 3. In the absence of renal compensation, this would be expected to result in approximately 40 g of sodium excretion/24 hours with normal kidney function. However, rapid tubular compensation occurred with increased sodium reabsorption both in the loop ( P < 0.001) and distal nephron ( P < 0.001). Inhibition of sodium-glucose cotransporter-2 did not attenuate over 14 days of empagliflozin ( P = 0.14). However, there were significant reductions in FELi ( P = 0.009), fractional excretion of sodium ( P = 0.004), and absolute fractional distal sodium reabsorption ( P = 0.036), indicating that chronic adaptation to SGLT2i results primarily from increased reabsorption in the loop and/or PT. CONCLUSIONS: Empagliflozin caused substantial redistribution of intrarenal sodium delivery and reabsorption, providing mechanistic substrate to explain some of the benefits of this class. Importantly, the large increase in sodium exit from the PT was balanced by distal compensation, consistent with SGLT2i excellent safety profile. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: ClinicalTrials.gov ( NCT03027960 ).

Decline in Estimated Glomerular Filtration Rate After Dapagliflozin in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial.

Importance: An initial decline in estimated glomerular filtration rate (eGFR) is expected after initiating a sodium-glucose cotransporter-2 inhibitor (SGLT2i) and has been observed across patients with diabetes, chronic kidney disease, and heart failure. Objective: To examine the implications of initial changes in eGFR among patients with heart failure with mildly reduced ejection fraction (HFmrEF) or preserved ejection fraction (HFpEF) enrolled in the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure (DELIVER) trial. Design, Setting, and Participants: This was a prespecified analysis of the results of the DELIVER randomized clinical trial, which was an international multicenter study of patients with EF greater than 40% and eGFR greater than or equal to 25. The DELIVER trial took place from August 2018 to March 2022. Data for the current prespecified study were analyzed from February to October 2023. Intervention: Dapagliflozin, 10 mg per day, or placebo. Main Outcomes and Measures: In this prespecified analysis, the frequency of an initial eGFR decline (baseline to month 1) was compared between dapagliflozin and placebo. Cox models adjusted for baseline eGFR and established prognostic factors were fit to estimate the association of an initial eGFR decline with cardiovascular (cardiovascular death or heart failure event) and kidney (≥50% eGFR decline, eGFR<15 or dialysis, death from kidney causes) outcomes, landmarked at month 1, stratified by diabetes. Results: Study data from 5788 participants (mean [SD] age, 72 [10] years; 3253 male [56%]) were analyzed. The median (IQR) change in eGFR level from baseline to month 1 was -1 (-6 to 5) with placebo and -4 (-9 to 1) with dapagliflozin (difference, -3; P < .001). A higher proportion of patients assigned to dapagliflozin developed an initial eGFR decline greater than 10% vs placebo (1144 of 2892 [40%] vs 737 of 2896 [25%]; odds ratio, 1.9; 95% CI, 1.7-2.1; P difference <.001). An initial eGFR decline of greater than 10% (vs ≤10%) was associated with a higher risk of the primary cardiovascular outcome among those randomized to placebo (adjusted hazard ratio [aHR], 1.33; 95% CI, 1.10-1.62) but not among those randomized to dapagliflozin (aHR, 0.90; 95% CI, 0.74-1.09; P for interaction = .01). Similar associations were observed when alternative thresholds of initial eGFR decline were considered and when analyzed as a continuous measure. An initial eGFR decline of greater than 10% was not associated with adverse subsequent kidney composite outcomes in dapagliflozin-treated patients (aHR, 0.94; 95% CI, 0.49-1.82). Conclusions and Relevance: Among patients with HFmrEF or HFpEF treated with dapagliflozin, an initial eGFR decline was frequent but not associated with subsequent risk of cardiovascular or kidney events. These data reinforce clinical guidance that SGLT2is should not be interrupted or discontinued in response to an initial eGFR decline. Trial Registration: ClinicalTrials.gov Identifier: NCT03619213.

Kidney and heart failure events are bidirectionally associated in patients with type 2 diabetes and cardiovascular disease.

AIMS: This study aimed to evaluate the bidirectional relationship between kidney and cardiovascular (CV) events in trial participants with type 2 diabetes and CV disease. METHODS AND RESULTS: Post hoc analyses of EMPA-REG OUTCOME using Cox regression models were performed to assess the association of baseline factors with risk of a kidney event and bidirectional associations of incident kidney events and CV events. Among placebo-treated participants, baseline factors significantly associated with greater kidney event risk included lower baseline estimated glomerular filtration rate, albuminuria, higher uric acid, low-density lipoprotein cholesterol levels, and prior heart failure (HF). Coronary artery disease was not associated with increased risk. In placebo-treated participants, occurrence of an incident non-fatal kidney event increased the subsequent risk of hospitalization for HF (HHF) but not 3-point major adverse CV events (non-fatal stroke, non-fatal myocardial infarction, and CV death). Vice versa, HHF (but not myocardial infarction/stroke) increased the risk of subsequent kidney events. These associations were generally also seen in empagliflozin-treated participants and in the overall population. Interestingly, the risk of kidney events following HHF was not significantly increased in the relatively small number of placebo-treated participants already diagnosed with HF at baseline. CONCLUSIONS: These findings demonstrate a bidirectional inter-relationship between HHF and kidney events. Further exploration of this relationship and strategies to optimize the use of therapies to reduce both kidney and HF outcomes is warranted.

Heart Failure, Investigator-Reported Sleep Apnea and Dapagliflozin: A Patient-Level Pooled Meta-Analysis of DAPA-HF and DELIVER.

BACKGROUND: Sleep apnea is more common in patients with heart failure (HF) than in the general population, but little is known about its association with clinical outcomes in various HF phenotypes or how it might modify the effect of HF therapy. OBJECTIVES: To examine the prevalence of sleep apnea, its association with outcomes and the effects of dapagliflozin in patients with HF with and without sleep apnea in a pooled analysis of 2 trials comparing dapagliflozin to placebo in HFrEF (DAPA-HF trial) and HFmrEF/HFpEF (DELIVER trial). METHODS: A history of sleep apnea was investigator-reported. The primary outcome was a composite of worsening HF or cardiovascular death. RESULTS: The prevalence of sleep apnea was 5.7% and 7.8% in patients with HFrEF and HFmrEF/HFpEF, respectively. The primary outcome occurred at a rate of 16.0 in participants with sleep apnea compared to 10.6 per 100 person-years in those without (adjusted HR 1.29 [95%CI, 1.10-1.52]). Compared with placebo, dapagliflozin reduced the risk of the primary endpoint to the same extent in patients with (HR 0.78 [95% CI, 0.59-1.03]) and without sleep apnea (HR 0.79 [0.72-0.87]) [Pinteraction = 0.93]. The beneficial effects of dapagliflozin on other clinical outcomes and symptom burden, physical function, and quality of life were consistent in participants with and without sleep apnea. CONCLUSIONS: In DAPA-HF and DELIVER, the true prevalence of sleep apnea was likely underestimated. An investigator-reported history of sleep apnea was associated with higher rates of worsening HF events. The benefits of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. CLINICAL TRIAL REGISTRATION: Unique identifiers: NCT01920711 CONDENSED ABSTRACT: In a pooled analysis of the DAPA-HF and DELIVER trials of more than 11,000 patients with heart failure (HF) across the range of ejection fractions, an investigator-reported history of sleep apnea was associated with higher rates of worsening HF events but not mortality. The beneficial effects of dapagliflozin on clinical outcomes were consistent in patients with and without sleep apnea. These findings provide further evidence for dapagliflozin as a new treatment option for patients with heart failure across the range of ejection fractions.