BACKGROUND:Inflammation may play an important pathophysiological role in the development and progression of heart failure (HF). Interleukin (IL)-6 is a circulating cytokine and is the main regulator of the release of C-reactive protein (CRP). OBJECTIVES:The authors examined the association between IL-6 and high-sensitivity (hs)-CRP and outcomes in patients with HFrEF in the DAPA-HF trial and their relationship with the effect of dapagliflozin. METHODS:Inclusion criteria included: 1) NYHA functional class II-IV; 2) left ventricular ejection fraction ≤40%; 3) elevated N-terminal pro-B-type natriuretic peptide; and 4) estimated glomerular filtration rate ≥30 mL/min/1.73 m2. The primary outcome was a composite of a worsening HF event or cardiovascular death. IL-6 and hs-CRP were measured at baseline and 12 months (Roche Diagnostics). The associations between IL-6 and hs-CRP and outcomes were adjusted for known prognostic variables, including NT-proBNP. RESULTS:Among 2,940 patients, median IL-6 and hs-CRP at baseline were 6.01 pg/mL (Q1-Q3: 4.18-9.28 pg/mL) and 2.05 mg/L (Q1-Q3: 0.83-4.9 mg/L), respectively. Baseline IL-6 tertiles (T) were: T1 ≤4.72 pg/mL; T2 4.73-7.89 pg/mL; and T3 ≥7.90 pg/mL. The adjusted risks of the primary outcome relative to T1 were as follows: T2 = HR 1.34 (95% CI: 1.04-1.73) and T3 = HR 1.80 (95% CI: 1.41-2.31). A rise in IL-6 between baseline and 12 months was associated with worse outcomes. The beneficial effect of dapagliflozin on the primary outcome was consistent regardless of IL-6 concentration (continuous interaction P = 0.57), with similar results for hs-CRP. Dapagliflozin did not reduce IL-6 or hs-CRP at 12 months. CONCLUSIONS:In DAPA-HF, elevated IL-6 and hs-CRP levels were each associated with the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of adverse outcomes regardless of baseline IL-6 or hs-CRP. (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).

BACKGROUND:Patients with severe heart failure (HF) experience debilitating clinical symptoms and worse cardiovascular (CV) outcomes with an excess mortality risk. OBJECTIVES:The authors aimed to assess the prevalence, CV outcome risk, and treatment response to the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin among patients with severe HF across the spectrum of left ventricular ejection fraction (LVEF) in DAPA-HF and DELIVER. METHODS:Severe HF was adapted from the ESC (European Society of Cardiology) HFA (Heart Failure Association) definition: NYHA functional class III/IV, evidence of HF with reduced, mildly reduced, or preserved LVEF, HF hospitalization within the previous 12 months, and adverse patient-reported symptom burden (Kansas City Cardiomyopathy Questionnaire-Total Symptoms Score <75). Outcomes and the treatment effect of dapagliflozin were assessed for the primary endpoint of CV death or first worsening HF event by severe HF status. RESULTS:Among 10,948 patients with available data to define severe HF, 730 (6.7%) fulfilled the severe HF definition (296/4,722 [6.2%] with LVEF ≤40%, 192/2,101 [9.1%] with LVEF 41%-49%, and 232/4,125 [5.6%] with LVEF ≥50%). Over a median follow-up of 22 months, the primary endpoint occurred in 231 patients, at a rate of 20 per 100 patient-years (Q1-Q3: 17-23 per 100 patient-years). Patients with severe HF experienced a higher rate of events than patients without severe HF (adjusted HR: 1.85; 95% CI: 1.60-2.12), regardless of LVEF (Pinteraction = 0.98). Treatment with dapagliflozin was consistently beneficial in reducing the risk of the primary endpoint regardless of severe HF status (Pinteraction = 0.48) across the LVEF spectrum (3-way Pinteraction = 0.52). The safety profile of dapagliflozin was also consistent regardless of the severe HF status. CONCLUSIONS:Severe HF was associated with an excess risk of CV events across the spectrum of LVEF. Treatment with the SGLT2i dapagliflozin appeared to be safe and effective in reducing the risk of CV death or worsening HF in this population. (Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure [DAPA-HF]; NCT03036124; Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [DELIVER]; NCT03619213).

BACKGROUND:Treatment with the sodium-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, attenuates progression of kidney disease and reduces the risks of heart failure and death in patients with chronic kidney disease (CKD). Data on the effects of dapagliflozin on health-related quality of life (HRQoL) are limited. METHODS:Adults with CKD, with and without type 2 diabetes, with estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m2 and urinary albumin-to-creatinine ratio 200-5000 mg/g were randomized to dapagliflozin (10 mg/day) or placebo. We assessed HRQoL using the Kidney Disease Quality of Life (KDQOL-36) questionnaire at baseline and at 12, 24, and 36 months. In this prespecified analysis, we determined the overall effects of dapagliflozin versus placebo. RESULTS:A total of 4032/4304 (94%) randomized participants (mean age 62(12) years, 32% female) had information on KDQOL-36 at baseline. Mean scores on the physical health composite (PHC); mental health composite (MHC); and kidney disease symptoms, effects, and burden were similar between randomized groups at baseline. During a median follow-up of 2.3 (Interquartile range: 1.9, 2.6) years, mean scores were significantly higher in participants randomized to dapagliflozin for PHC (0.71 [95% CI: 0.30, 1.31]), MHC (0.62 [95%CI: 0.14, 1.11]) kidney disease symptoms (1.33 [95% CI: 0.57, 2.10]), kidney disease effects (1.34 [95% CI: 0.43, 2.26]) and kidney disease burden (1.46 [95%CI: 0.30, 2.62]). Participants randomized to dapagliflozin were significantly less likely to experience a clinically meaningful (≥10 units) decline in PHC relative to placebo (hazard ratio [HR] 0.84 (95% CI: 0.74, 0.96). Corresponding HRs for ≥10-unit decline in MHC, and kidney disease symptoms, effects, and burden were 0.95 (95% CI: 0.85, 1.07), 0.84 (95% CI: 0.75, 0.94), and 0.84 (95% CI: 0.72, 0.97) and 0.93 (95% CI: 0.84, 1.02), respectively. CONCLUSIONS:In participants with CKD with and without type 2 diabetes, treatment with dapagliflozin slowed the decline in physical health, reduced worsening of symptoms, and lessened the effect of kidney disease.

Importance:Vascular cell adhesion molecule 1 (VCAM-1) and intracellular cell adhesion molecule 1 (ICAM-1) are responsible for immune cell-cell interactions. Systemic levels of VCAM-1 are associated with incident heart failure (HF). Objectives:To determine if VCAM-1 and ICAM-1 levels are associated with progression of established HF. Design, Setting, and Participants:Participants enrolled in the biomarker substudy of the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) randomized clinical trial had VCAM-1 and ICAM-1 levels measured at baseline and 12 months. The DAPA-HF trial was conducted at 410 sites in 20 countries. Patients with HF and reduced ejection fraction (HFrEF) in New York Heart Association (NYHA) class II to IV with elevated natriuretic peptides were enrolled between February 15, 2017, and August 17, 2018, with final follow-up on June 6, 2019. Data were analyzed from January 2023 to January 2025. Interventions:Dapagliflozin, 10 mg, once daily vs placebo. Main Outcomes and Measures:The primary outcome was the composite of a worsening HF event or cardiovascular death. The associations between VCAM-1 and ICAM-1 levels at baseline and the primary outcome, its components, and all-cause death were analyzed using Cox proportional hazards regression models adjusted for known prognostic variables including estimated glomerular filtration rate (eGFR), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and high-sensitivity troponin T (hs-TnT), as well as high-sensitivity C-reactive protein. Results:A total of 3051 participants (mean [SD] age, 67.2 [10.5] years; 2386 male [78.2%]) were included in this study. Mean (SD) follow-up time was 17.6 (5.2) months. The median (IQR) baseline VCAM-1 level was 997 (816.7-1218.8) ng/mL. Compared with patients with lower concentrations of VCAM-1, those with higher concentrations of VCAM-1 were older (mean [SD] age T3 vs T1, 69.7 [9.7] years vs 64.1 [10.7] years; P < .001), in worse NYHA class (T3 vs T1, NYHA class III/IV 35.6% [362 of 1017] vs 26.5% [269 of 1017]; P < .001), and had higher NT-proBNP (median [IQR] T3 vs T1, 2018 [1126-3753] pg/mL vs 1118 [693-1830] pg/mL) and hs-TnT (median [IQR] T3 vs T1, 24.7 [17.1-37.5] ng/L vs 16.6 [11.6-24.9] ng/L) concentrations, and lower eGFR (mean [SD] T3 vs T1, 58.4 [17.6] mL/min/1.73 m2 vs 71.7 [18.0] mL/min/1.73 m2). Patients in tertile 3 of VCAM-1, compared with tertile 1, had the highest risk of each outcome (eg, adjusted hazard ratio [HR] for primary outcome 1.40; 95% CI, 1.11-1.77; P = .004). ICAM-1 level was not associated with an elevated risk of any outcome. The benefit of dapagliflozin vs placebo in reducing the risk of the primary outcome was consistent across VCAM-1 tertiles: HR, 0.76 (95% CI, 0.54-1.06), 0.82 (95% CI, 0.59-1.12), and 0.77 (95% CI, 0.61-0.98) for tertiles 1, 2 and 3, respectively (P for interaction = .93). There was no significant change in VCAM-1 level with dapagliflozin at 52 weeks. Conclusions and Relevance:Results of this substudy of the DAPA-HF randomized clinical trial demonstrate that higher VCAM-1 levels, possibly reflecting a distinct inflammatory/immune pathophysiological pathway in HFrEF, were associated with worse outcomes, even after adjustment for conventional prognostic variables. Trial Registration:ClinicalTrials.gov Identifier: NCT03036124.

Inflammation may play an important pathophysiological role in the development and progression of heart failure (HF). Interleukin (IL)-6 is a circulating cytokine and is the main regulator of the release of C-reactive protein (CRP). The authors examined the association between IL-6 and high-sensitivity (hs)-CRP and outcomes in patients with HFrEF in the DAPA-HF trial and their relationship with the effect of dapagliflozin. Inclusion criteria included: 1) NYHA functional class II-IV; 2) left ventricular ejection fraction ≤40%; 3) elevated N-terminal pro-B-type natriuretic peptide; and 4) estimated glomerular filtration rate ≥30 mL/min/1.73 m2. The primary outcome was a composite of a worsening HF event or cardiovascular death. IL-6 and hs-CRP were measured at baseline and 12 months (Roche Diagnostics). The associations between IL-6 and hs-CRP and outcomes were adjusted for known prognostic variables, including NT-proBNP. Among 2,940 patients, median IL-6 and hs-CRP at baseline were 6.01 pg/mL (Q1-Q3: 4.18-9.28 pg/mL) and 2.05 mg/L (Q1-Q3: 0.83-4.9 mg/L), respectively. Baseline IL-6 tertiles (T) were: T1 ≤4.72 pg/mL; T2 4.73-7.89 pg/mL; and T3 ≥7.90 pg/mL. The adjusted risks of the primary outcome relative to T1 were as follows: T2 = HR 1.34 (95% CI: 1.04-1.73) and T3 = HR 1.80 (95% CI: 1.41-2.31). A rise in IL-6 between baseline and 12 months was associated with worse outcomes. The beneficial effect of dapagliflozin on the primary outcome was consistent regardless of IL-6 concentration (continuous interaction P = 0.57), with similar results for hs-CRP. Dapagliflozin did not reduce IL-6 or hs-CRP at 12 months. In DAPA-HF, elevated IL-6 and hs-CRP levels were each associated with the risk of worsening HF or cardiovascular death. Dapagliflozin reduced the risk of adverse outcomes regardless of baseline IL-6 or hs-CRP. (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).

AIMS:In the randomized DAPA-MI clinical trial, 10 mg of dapagliflozin once daily improved cardiometabolic outcomes versus placebo after acute myocardial infarction (MI) in patients without established diabetes or heart failure (HF). We assessed associations between baseline left ventricular ejection fraction (LVEF) and cardiometabolic outcomes in DAPA-MI. METHODS:The primary outcome, assessed using the win ratio method, was the hierarchical composite of death, hospitalization for HF, non-fatal MI, atrial fibrillation/flutter, Type 2 diabetes, New York Heart Association classification at last visit and body weight decrease of ≥5% from baseline to last visit. For the present analysis, patients were categorized using LVEF at randomization (<50% or ≥50%). RESULTS:Of the DAPA-MI participants with available LVEF data who received ≥1 dose of study drug (n = 3751), 2913 (77.7%) had LVEF <50% and 838 (22.3%) had LVEF ≥50%. The primary hierarchical composite outcome resulted in a win ratio favouring dapagliflozin of 1.38 (95% CI: 1.21, 1.57; P < 0.001) in patients with LVEF <50% and 1.32 (1.00, 1.73; P = 0.048) in patients with LVEF ≥ 50% (P interaction = 0.76). In a sensitivity analysis excluding patients with LVEF <30%, the primary hierarchical composite outcome resulted in a win ratio favouring dapagliflozin of 1.40 (95% CI: 1.22, 1.61; P < 0.001). There were no significant interactions between baseline LVEF and any secondary outcomes. CONCLUSIONS:Regardless of baseline LVEF, dapagliflozin resulted in significant cardiometabolic benefits versus placebo, although there was no impact on the composite of cardiovascular death or hospitalization for HF.

Although several previous studies tested SGLT2 inhibitors in the setting of an acute, non-cardiovascular illness, detailed information on their efficacy and safety among participants with and without type 2 diabetes (T2D) from double-blind randomized trials is lacking. In this secondary prespecified analysis of the Dapagliflozin in Respiratory Failure in Patients with COVID-19 (DARE-19) trial, we sought to evaluate the safety and efficacy of initiating dapagliflozin during acute illness with COVID-19 in patients with and without T2D. The DARE-19 trial randomized 1250 patients hospitalized with COVID-19 and cardiometabolic risk factors to dapagliflozin or placebo. T2D was present in 636/1250 (50.9

Background Dapagliflozin improved cardiometabolic outcomes following myocardial infarction in patients without prior type‐2 diabetes (T2DM) in the DAPA‐MI (dapagliflozin in patients with myocardial infarction) trial. The effect of glycemic status and body mass index (BMI) post–myocardial infarction requires elucidation. Methods Participants with T2DM diagnosis, without baseline hemoglobin A1c, or not receiving any study medication, were excluded. Eligible participants were categorized, according to baseline hemoglobin A1c, as normoglycemic (<5.7% [39 mmol/mol]) or prediabetes (5.7 to <6.5% [48 mmol/mol]) and according to baseline BMI (<25, 25 to <30, and ≥30 kg/m2). Hazard ratios (HRs) with 95% CIs and 1‐year Kaplan–Meier rates were determined for new‐onset T2DM (investigator‐reported or hemoglobin A1c ≥6.5%) and New York Heart Association symptom classification during follow‐up. Results Of 4017 DAPA‐MI participants, 3425 were eligible. In 1926 with baseline normoglycemia, new‐onset T2DM occurred in 0.6% and 1.6% assigned to dapagliflozin and placebo, respectively (hazard ratio, 0.40 [95% CI, 0.15–1.03]); in 1499 with prediabetes at baseline, new‐onset T2DM occurred in 10.1% and 13.1%, respectively (hazard ratio, 0.74 [05% CI, 0.55–0.99]; P interaction 0.23). One‐year absolute risk reduction for new‐onset T2DM was 8.1% in those with both prediabetes and BMI ≥30. Dapagliflozin reduced the occurrence of New York Heart Association class III–IV symptoms, with greater effect in those with prediabetes versus normoglycemia (P interaction 0.009). One‐year absolute risk reduction for New York Heart Association class III–IV symptoms was 10.0% in those with both prediabetes and BMI ≥30. Conclusions Dapagliflozin reduced the occurrence of new‐onset T2DM following myocardial infarction, regardless of baseline hemoglobin A1c or BMI. Dapagliflozin provided greater reduction in heart failure symptom burden in those with prediabetes compared with normoglycemia.

INTRODUCTION:Wearable accelerometers allow continuous assessment of physical activity during normal living conditions and may be useful in evaluating the effects of treatment for heart failure. We explored the relationships between accelerometer measures of physical activity and 6-minute walk distance and patient-reported measures of functional limitation in participants across the entire spectrum of left ventricular ejection fraction in the DETERMINE (Dapagliflozin EffecT on ExeRcise capacity using a 6-MINutE walk test in patients with heart failure) trials. METHODS:A subgroup of patients in the DETERMINE trials wore a waist-based accelerometer during 7-day periods at 3 points during the trial: between screening and randomization and during weeks 8 and 14. Patients completed the Kansas City Cardiomyopathy Questionnaire (KCCQ) and 6-minute walk distance (6MWD) at baseline and at weeks 8 and 16. RESULTS:Of the 817 patients randomized, 319 (39%) had adequate baseline accelerometer data. Patients with lower levels of physical activity had lower (ie, worse) KCCQ scores and 6MWD, higher NT-proBNP levels and BMIs, worse kidney function, and a greater likelihood of diabetes and atrial fibrillation. Baseline accelerometer values had weak correlations with KCCQ summary scores (Pearson r = 0.06-0.21) and weak to moderate correlations with 6MWD (Pearson r = 0.20-0.31). The change from baseline to 16 weeks in accelerometer-measured physical activity correlated weakly with the change in KCCQ summary scores (Pearson r = 0-0.18) and 6MWD (r = 0.01-0.10). CONCLUSIONS:In the DETERMINE trials, accelerometer-based measures of physical activity correlated modestly with KCCQ summary scores and 6MWD. Accelerometer-based assessments of physical activity may provide additional information complementing that obtained from standard measures of functional limitation in patients with heart failure.

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.

BackgroundHigher temperatures are associated with higher rates of hospital admissions for nephrolithiasis and acute kidney injury. Occupational heat stress is also a risk factor for kidney dysfunction in resource-poor settings. It is unclear whether ambient heat exposure is associated with loss of kidney function in patients with established chronic kidney disease. We assessed the association between heat index and change in estimated glomerular filtration rate (eGFR) in participants from the DAPA-CKD trial in a post-hoc analysis.MethodsDAPA-CKD was a randomised controlled trial of oral dapagliflozin 10 mg once daily or placebo that enrolled participants aged 18 years or older, with or without type 2 diabetes, with a urinary albumin-to-creatinine ratio of 200–5000 mg/g, and an eGFR of 25–75 mL/min per 1·73 m2. In this post-hoc analysis, we explored the association between time-varying daily centre-level heat index (ERA5 dataset) and individual-level change in eGFR in trial participants using linear mixed effect models and case-time series. The DAPA-CKD trial is registered with ClinicalTrials.gov, NCT03036150.FindingsClimate and eGFR data were available for 4017 (93·3%) of 4304 participants in 21 countries (mean age: 61·9 years; mean eGFR: 43·3 mL per 1·73 m2; median 28 months follow-up). Across centres, a heat index of more than 30°C occurred on a median of 0·6% of days. In adjusted linear mixed effect models, within each 120-day window, each 30 days’ heat index of more than 30°C was associated with a –0·6% (95% CI –0·9% to –0·3%) change in eGFR. Similar estimates were obtained using case-time series. Additional analyses over longer time-windows showed associations consistent with haemodynamic or seasonal variability, or both, but overall estimates corresponded to an additional 3·7 mL per 1·73 m2 (95% CI 0·1 to 7·0) loss of eGFR per year in a patient with an eGFR of 45 mL per 1·73 m2 located in a very hot versus a temperate environment.InterpretationHigher ambient heat exposure is associated with more rapid eGFR decline in those with established chronic kidney disease. Efforts to mitigate heat exposure should be tested as part of strategies to attenuate chronic kidney disease progression.FundingNone.

BACKGROUND AND AIMS:Individuals with heart failure (HF), other forms of cardiovascular disease, or kidney disease are at increased risk for the development and adverse health effects of diabetes. As such, prevention or delay of diabetes is an important treatment priority in these groups. The aim of this meta-analysis was to determine the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on incident diabetes in HF across the spectrum of left ventricular ejection fraction (LVEF) and across the broader spectrum of cardiovascular or kidney disease. METHODS:First, the effects of dapagliflozin vs. placebo on new-onset diabetes were assessed in a pooled, participant-level analysis of the DAPA-HF and DELIVER trials. New-onset diabetes was defined as the new initiation of glucose-lowering therapy during follow-up, and time from randomization to new-onset diabetes was evaluated using Cox proportional hazards models. Second, PubMed and Embase were searched to identify large-scale randomized clinical outcomes trials (RCTs) comparing SGLT2i with placebo among adults with cardiovascular or kidney disease. A trial-level meta-analysis was then conducted to summarize the treatment effects of SGLT2i on the incidence of new-onset diabetes. RESULTS:In the pooled analysis of DAPA-HF and DELIVER including 5623 participants with HF but without diabetes at baseline, dapagliflozin reduced the incidence of new-onset diabetes by 33% [hazard ratio (HR), 0.67; 95% confidence interval (CI), .49-.91; P = .012] when compared with placebo. There was no evidence of heterogeneity across the spectrum of continuous LVEF or key subgroups. Among seven complementary RCTs including 17 855 participants with cardiovascular or kidney disease, SGLT2i reduced the of new-onset diabetes by 26% (HR, 0.74; 95% CI .65-.85; P < .001), with consistent effects across trials. CONCLUSIONS:SGLT2i reduced the incidence of new-onset diabetes among individuals with cardiovascular or kidney disease. These findings suggest that SGLT2i implementation may have an important ancillary benefit on prevention or delay of diabetes in these high-risk populations.

ImportanceAn 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.ObjectiveTo 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 ParticipantsThis 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.InterventionDapagliflozin, 10 mg per day, or placebo.Main Outcomes and MeasuresIn 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.ResultsStudy 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 RelevanceAmong 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 RegistrationClinicalTrials.gov Identifier: NCT03619213

AimsType 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 resultsDELIVER 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.ConclusionsDapagliflozin 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.

Despite the provision of renin-angiotensin-aldosterone-system inhibitors and immunosuppressive therapies, membranous nephropathy often progresses to kidney failure. The objective of this pre-specified analysis was to assess the safety and efficacy of dapagliflozin in patients with membranous nephropathy enrolled in the DAPA-CKD trial.

Background: Patients with severe heart failure (HF) experience debilitating clinical symptoms and worse cardiovascular (CV) outcomes with an excess mortality risk. Until recently, severe HF has largely been considered only in those with reduced ejection fraction. The ESC HFA has put forth a consensus definition for severe or advanced HF that may be applicable across the ejection fraction (EF) spectrum. Hypothesis: Patients with severe HF experience a higher rate of CV outcomes. The safety and efficacy of SGLT2i dapagliflozin is consistent regardless of the severe HF status. Aims: To assess the prevalence, CV outcome risk, and treatment response to the SGLT2i dapagliflozin among patients with severe HF. Methods: DAPA-HF and DELIVER were randomized, double-blind trials, testing dapagliflozin vs placebo in 11,007 patients with symptomatic HF across the full spectrum of EF. Severe HF was adapted from the ESC HFA definition: NYHA class III/IV, evidence of HF with reduced, mildly reduced or preserved EF, elevated natriuretic peptides, HF hospitalization within previous 12 months, and adverse patient-reported symptom burden (KCCQ-TSS<75). Outcomes were assessed and the treatment effect of dapagliflozin was measured for the primary endpoint of CV death or first worsening HF event (including HF hospitalization and urgent HF visit) by severe HF status. Results: Overall, 730 (6.6%) fulfilled the severe HF definition (296 [40.6%] with EF ≤40%, 192 [26.3%] with EF 41-49%, and 232 [33.2%] with EF ≥50%). Patients with severe HF had a higher comorbidity burden and higher NT-proBNP values. Over a median follow-up of 22.4 months, the primary endpoint occurred in 231 patients, at a rate of 20 (17-23) per 100py. Patients with severe HF experienced a higher rate of events compared to patients without severe HF (adjusted hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.20-1.75), across the spectrum of LVEF (P interaction =0.85). Treatment with dapagliflozin was consistently beneficial in reducing the risk of the primary endpoint regardless of the severe HF status (P interaction =0.10, Figure 1 ). The safety profile of dapagliflozin was also consistent irrespective of the severe HF status ( Figure 2 ). Conclusions: In a large, global contemporary HF trial population, “severe HF” was associated with excess risk of CV events across the spectrum of EF. Treatment with the SGLT2i dapagliflozin appears safe and effective in reducing the risk of CV death or worsening HF in this population.

BACKGROUND:Wearable accelerometers can quantify the frequency and intensity of physical activity during everyday life and may provide complementary data to established functional outcome measures on the effect of heart failure therapies on functional limitations.METHODS:In a voluntary substudy of the DETERMINE trials (Dapagliflozin Effect on Exercise Capacity Using a 6-Minute Walk Test in Patients With Heart Failure), patients wore a waist-worn triaxial accelerometer for as long as possible (ideally for 24 h/d for 7 days) at 3 points during the trial, between the screening visit and randomization (baseline data), and during weeks 8 and 14 to 16. Accelerometer outcomes included the change from baseline to week 16 in the total number of steps, time spent in light-to-vigorous physical activity, time spent in moderate-to-vigorous physical activity, movement intensity during walking, number of vector magnitude units, and total activity counts.RESULTS:Adequate baseline and week 16 accelerometer data were available for 211 of 817 (26%) randomized patients (defined as >= 10 hours of wear time for >= 3 days). Dapagliflozin had a favorable effect on the mean change from baseline at 16 weeks in the number of steps (between-group difference, 778 [95% CI, 240-1315]), time spent in moderate-to-vigorous physical activity (0.16 [95% CI, 0.03-0.29] hours), and in the mean vector magnitude units (25 [95% CI, 0.1-49] counts per minute). There were no between-group differences in the other accelerometer outcomes of interest.CONCLUSIONS:In this exploratory analysis of the DETERMINE trials, dapagliflozin had a beneficial effect on selected accelerometer-based measures of physical activity in patients with heart failure across the entire left ventricular ejection fraction spectrum, yet did not improve 6-minute walk distance, as previously reported. These data suggest that accelerometer-based measurements of everyday activity may provide complementary information to 6-minute walk distance and identify beneficial effects of treatment not detected by 6-minute walk distance.REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifiers: NCT03877237 and NCT03877224.

Background and Aims Sodium-glucose cotransporter 2 inhibitors decrease blood pressure in patients with type 2 diabetes, but the consistency and magnitude of blood pressure lowering with dapagliflozin in patients with chronic kidney disease (CKD) is unknown. We conducted a prespecified analysis of the DAPA-CKD trial to investigate the effect of dapagliflozin on systolic blood pressure (SBP) in patients with CKD, with and without type 2 diabetes. Methods A total of 4304 adults with baseline estimated glomerular filtration rate (eGFR) 25-75 mL/min/1.73m 2 and urinary albumin-to-creatinine ratio (UACR) 200-5000 mg/g were randomized to either dapagliflozin 10 mg or placebo once daily; median follow-up was 2.4 years. The primary endpoint was a composite of sustained >= 50% eGFR decline, end-stage kidney disease, or death from a kidney or cardiovascular cause. Change in SBP was a prespecified outcome. Results Baseline mean (SD) SBP was 137.1 mmHg (17.4). By Week 2, dapagliflozin compared to placebo reduced SBP by 3.6 mmHg (95% CI 2.8-4.4 mmHg), an effect maintained over the duration of the trial (2.9 mmHg, 2.3-3.6 mmHg). Time-averaged reductions in SBP were 3.2 mmHg (2.5-4.0 mmHg) in patients with diabetes and 2.3 mmHg (1.2-3.4 mmHg) in patients without diabetes. The time-averaged effect of dapagliflozin on diastolic blood pressure (DBP) was 1.0 mmHg (0.6-1.4 mmHg); 0.8 mmHg (0.4-1.3 mmHg) in patients with diabetes and 1.4 mmHg (0.7-2.1 mmHg) in patients without diabetes. Benefits of dapagliflozin on the primary composite and secondary endpoints were evident across the spectrum of baseline SBP and DBP. Conclusion In patients with CKD and albuminuria, randomization to dapagliflozin was associated with modest reductions in systolic and diastolic BP. (Am Heart J 2024;270:125-135.)