Towards quadruple therapy for heart failure with reduced ejection fraction: DAPA-HF secondary analysis data

Objective The SGLT2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the <a>Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure </a>trial (DAPA-HF). This report explores the effect of dapagliflozin on incident type 2 diabetes in the non-diabetic cohort enrolled in the trial. Research Design/Methods The subgroup of 2605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and a HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model. Results At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93/1307 patients (7.1%) in the placebo group and 64/1298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (HR 0.68, 95% CI, 0.50-0.94; p=0.019.) More than 95% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5.7-6.4%.) Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not. Conclusions In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.

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Dapagliflozin and the Incidence of Type 2 Diabetes in Patients With Heart Failure and Reduced Ejection Fraction: An Exploratory Analysis From DAPA-HF

10.2337/figshare.13235543.v1 ◽

2020 ◽

Author(s):

Silvio E Inzucchi ◽

Kieran F Docherty ◽

Lars Køber ◽

Mikhail N Kosiborod ◽

Felipe A Martinez ◽

...

Keyword(s):

Heart Failure ◽

Type 2 Diabetes ◽

Ejection Fraction ◽

Sglt2 Inhibitor ◽

Adverse Outcomes ◽

Exploratory Analysis ◽

Diabetes Incidence ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure

Objective The SGLT2 inhibitor dapagliflozin reduced the risk of cardiovascular mortality and worsening heart failure in the <a>Dapagliflozin and Prevention of Adverse-Outcomes in Heart Failure </a>trial (DAPA-HF). This report explores the effect of dapagliflozin on incident type 2 diabetes in the non-diabetic cohort enrolled in the trial. Research Design/Methods The subgroup of 2605 patients with heart failure and reduced ejection fraction (HFrEF), no prior history of diabetes, and a HbA1c of <6.5% at baseline was randomized to dapagliflozin 10 mg daily or placebo. In this exploratory analysis, surveillance for new onset diabetes was accomplished through periodic HbA1c testing as part of the study protocol and comparison between the treatment groups assessed through a Cox proportional hazards model. Results At baseline, the mean HbA1c was 5.8%. At 8 months, there were minimal changes, with a placebo-adjusted change in the dapagliflozin group of -0.04%. Over a median follow-up of 18 months, diabetes developed in 93/1307 patients (7.1%) in the placebo group and 64/1298 (4.9%) in the dapagliflozin group. Dapagliflozin led to a 32% reduction in diabetes incidence (HR 0.68, 95% CI, 0.50-0.94; p=0.019.) More than 95% of the participants who developed type 2 diabetes had prediabetes at baseline (HbA1c 5.7-6.4%.) Participants who developed diabetes in DAPA-HF had a higher subsequent mortality than those who did not. Conclusions In this exploratory analysis among patients with HFrEF, treatment with dapagliflozin reduced the incidence of new diabetes. This potential benefit needs confirmation in trials of longer duration and in people without heart failure.

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Dapagliflozin reduces the risk of hyperkalaemia in patients with heart failure and reduced ejection fraction: a secondary analysis DAPA-HF

European Heart Journal ◽

10.1093/ehjci/ehaa946.0939 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

S.L Kristensen ◽

K.F Docherty ◽

P.S Jhund ◽

O Bengtsson ◽

D.L Demets ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Cox Regression ◽

Secondary Analysis ◽

Adverse Outcomes ◽

Funding Source ◽

Private Company ◽

Reduced Ejection Fraction ◽

Life Saving ◽

Patients With Heart Failure

Abstract Background Hyperkalaemia often limits the use of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure and reduced ejection fraction (HFrEF), denying these patients a life-saving therapy. Purpose To determine whether treatment with the sodium-glucose cotransporter 2 (SGLT-2) inhibitor dapagliflozin reduces the risk of hyperkalaemia associated with MRA use in patients with HFrEF. Methods The risk of developing mild hyperkalaemia (potassium >5.5 mmol/L) and moderate/severe hyperkalaemia (>6.0 mmol/L) was examined in the Dapagliflozin And Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF) according to background MRA use, and randomized treatment assignment, by use of Cox regression analyses. Results Overall, 3370 (70.1%) patients in DAPA-HF were treated with an MRA. Mild hyperkalaemia and moderate/severe hyperkalaemia occurred in 182 (11.1%) and 23 (1.4%) patients treated with dapagliflozin as compared to 204 (12.6%) and 40 (2.4%) of patients given placebo (Table and Figure). This yielded a hazard ratio (HR) of 0.86 (0.70–1.05) for mild hyperkalaemia and 0.50 (0.29, 0.85) for moderate/severe hyperkalaemia, comparing dapagliflozin to placebo. Conclusions Patients with HFrEF and taking a MRA who were randomized to dapagliflozin had half the incidence of moderate/severe hyperkalaemia, compared with those randomized to placebo. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): DAPA-HF study was funded by AstraZeneca

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The Role of Sodium-Glucose Cotransporter-2 Inhibitors in Patients With Heart Failure, Regardless of Diabetes Status: Focus on Cardiovascular Disease

Annals of Pharmacotherapy ◽

10.1177/1060028020985111 ◽

2021 ◽

pp. 106002802098511

Author(s):

Filipe Ferrari ◽

Vítor M. Martins ◽

Rafael S. Scheffel ◽

Anderson D. da Silveira ◽

Marcelo Trotte Motta ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Data Extraction ◽

Sglt2 Inhibitor ◽

Sglt2 Inhibitors ◽

Reduced Ejection Fraction ◽

Sodium Glucose Cotransporter ◽

Diabetes Status ◽

Neprilysin Inhibitor ◽

Patients With Heart Failure

Objective: To provide clinical guidance and an overview of the available data on the use of sodium-glucose cotransporter-2 (SGLT2) inhibitors in patients with heart failure with reduced ejection fraction (HFrEF), regardless of the presence of type 2 diabetes mellitus (T2DM). Data Sources: We searched the MEDLINE database via PubMed (from January 2015 to November 2020) for the following key terms: SGLT2 inhibitors, sodium-glucose co-transporter-2 inhibitors, SGLT2i, heart failure, and heart failure with reduced ejection fraction. Study Selection and Data Extraction: To be included in the review, the articles needed to assess the effects of SGLT2 inhibitors in the heart failure (HF) scenario. Data Synthesis: There is consistent evidence that SGLT2 inhibitors reduce the risk of major adverse cardiovascular (CV) events and hospitalization in patients with HFrEF, even in the absence of T2DM. On May 5, 2020, the U.S. Food and Drug Administration approved dapagliflozin for adults with HFrEF, regardless of the presence of T2DM, even in those patients on standard therapy, including an angiotensin receptor/neprilysin inhibitor. Relevance to Patient Care and Clinical Practice: The SGLT2 inhibitors are well tolerated, and their once-daily dosing without the need for adjustments is convenient. These drugs can be considered a major breakthrough in pharmacotherapy for HF, providing physicians with a new treatment approach to reduce major clinical outcomes. Conclusions: SGLT2 inhibitor therapy reduces CV death and hospitalizations in HFrEF patients regardless of T2DM. The decision to prescribe this class of drugs should not be determined by glycemic status.

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Efficacy of Dapagliflozin on Renal Function and Outcomes in Patients with Heart Failure with Reduced Ejection Fraction: Results of DAPA-HF

Circulation ◽

10.1161/circulationaha.120.050391 ◽

2020 ◽

Cited By ~ 4

Author(s):

Pardeep S. Jhund ◽

Scott D. Solomon ◽

Kieran F. Docherty ◽

Hiddo J.L. Heerspink ◽

Inder S. Anand ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Kidney Function ◽

Adverse Outcomes ◽

Renal Outcome ◽

Pharmacological Management ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure ◽

Rate Of Decline

Background: Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease (CKD) which complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on kidney function after randomization. Many patients with heart failure and reduced ejection fraction (HFrEF) have chronic kidney disease (CKD) which complicates pharmacological management and is associated with worse outcomes. We assessed the safety and efficacy of dapagliflozin in patients with HFrEF, according to baseline kidney function, in the Dapagliflozin and Prevention of Adverse-outcomes in Heart Failure trial (DAPA-HF). We also examined the effect of dapagliflozin on kidney function after randomization. Methods: HFrEF patients with or without type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m 2 were enrolled in DAPA-HF. We calculated the incidence of the primary outcome (CV death or worsening HF) according to eGFR category at baseline (<60 and ≥60 ml/min/1.73m 2 ) as well as using eGFR at baseline as a continuous measure. Secondary cardiovascular outcomes and a pre-specified composite renal outcome (≥ 50% sustained decline eGFR, end stage renal disease (ESRD) or renal death) were also examined, along with decline in eGFR over time. Results: Of 4742 with a baseline eGFR, 1926 (41%) had eGFR <60 ml/min/1.73m 2 . The effect of dapagliflozin on the primary and secondary outcomes did not differ by eGFR category or examining eGFR as a continuous measurement. The hazard ratio (95% confidence interval (CI)) for the primary endpoint in patients with CKD was 0.71 (0.59, 0.86) vs. 0.77 (0.64, 0.93) in those with an eGFR ≥60 ml/min/1.73m 2 (interaction p=0.54). The composite renal outcome was not reduced by dapagliflozin (HR=0.71, 95% CI 0.44, 1.16; p=0.17) but the rate of decline in eGFR between day 14 and 720 was less with dapagliflozin, -1.09 (-1.41, -0.78) vs. placebo -2.87 (-3.19, -2.55) ml/min/1.73m 2 per year (p<0.001). This was observed in those with and without type 2 diabetes (p for interaction=0.92) Conclusions: Baseline kidney function did not modify the benefits of dapagliflozin on morbidity and mortality in HFrEF and dapagliflozin slowed the rate of decline in eGFR, including in patients without diabetes. Clinical Trial Registration: https://clinicaltrials.gov Unique Identifier: NCT03036124

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CHA2DS2-VASc score and adverse outcomes in patients with heart failure with reduced ejection fraction and sinus rhythm

European Journal of Heart Failure ◽

10.1002/ejhf.613 ◽

2016 ◽

Vol 18 (10) ◽

pp. 1261-1266 ◽

Cited By ~ 14

Author(s):

Siqin Ye ◽

Min Qian ◽

Bo Zhao ◽

Richard Buchsbaum ◽

Ralph L. Sacco ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Sinus Rhythm ◽

Adverse Outcomes ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure

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Optimizing Guideline-directed Medical Therapies for Heart Failure with Reduced Ejection Fraction During Hospitalization

US Cardiology Review ◽

10.15420/usc.2020.29 ◽

2021 ◽

Vol 15 ◽

Author(s):

Neal M Dixit ◽

Shivani Shah ◽

Boback Ziaeian ◽

Gregg C Fonarow ◽

Jeffrey J Hsu

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Outpatient Setting ◽

Evidence Based ◽

Mineralocorticoid Receptor Antagonists ◽

Reduced Ejection Fraction ◽

Sodium Glucose Cotransporter ◽

Neprilysin Inhibitor ◽

Patients With Heart Failure ◽

Annual Direct Cost

Heart failure remains a huge societal concern despite medical advancement, with an annual direct cost of over $30 billion. While guideline-directed medical therapy (GDMT) is proven to reduce morbidity and mortality, many eligible patients with heart failure with reduced ejection fraction (HFrEF) are not receiving one or more of the recommended medications, often due to suboptimal initiation and titration in the outpatient setting. Hospitalization serves as a key point to initiate and titrate GDMT. Four evidence-based therapies have clinical benefit within 30 days of initiation and form a crucial foundation for HFrEF therapy: renin-angiotensin-aldosterone system inhibitors with or without a neprilysin inhibitor, β-blockers, mineralocorticoid-receptor-antagonists, and sodium-glucose cotransporter-2 inhibitors. The authors present a practical guide for the implementation of these four pillars of GDMT during a hospitalization for acute heart failure.

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Dapagliflozin in a Real-World Chronic Heart Failure Population: How Many Are Actually Eligible?

Cardiology ◽

10.1159/000512432 ◽

2021 ◽

pp. 1-6

Author(s):

Sérgio Maltês ◽

Gonçalo J.L. Cunha ◽

Bruno M.L. Rocha ◽

João Presume ◽

Renato Guerreiro ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Real World ◽

Left Ventricular ◽

Left Ventricular Ejection ◽

Ventricular Ejection Fraction ◽

Disease Modifying Drugs ◽

Reduced Ejection Fraction ◽

Sodium Glucose Cotransporter ◽

Patients With Heart Failure

Background: In patients with heart failure (HF) and reduced ejection fraction (HFrEF) with or without type 2 diabetes mellitus, the sodium-glucose cotransporter 2 inhibitor (SGLT2i) dapagliflozin was recently shown to reduce the risk of worsening HF or death from cardiovascular causes in the dapagliflozin in patients with heart failure and reduced ejection fraction (DAPA-HF) trial. Our goal was to investigate how many patients in a real-world setting would be eligible for dapagliflozin according to the DAPA-HF enrolment criteria. Methods: This is a single-center retrospective study enrolling consecutive, unselected patients followed up in an HF clinic from 2013 to 2019. Key DAPA-HF inclusion criteria (i.e., left ventricular ejection fraction [LVEF] ≤40% and NT-proBNP ≥600 pg/mL [or ≥900 pg/mL if atrial fibrillation]) and exclusion criteria (estimated glomerular filtration rate [eGFR] <30 mL/kg/1.73 m2 and systolic blood pressure [SBP] <95 mm Hg) were considered. Results: Overall, 479 patients (age 76 ± 13 years; 50.5% male; 78.9% hypertensive; 45.1% with an eGFR <60 mL/min/1.73 m2; 36.5% with TD2M; and 33.5% with ischaemic HF) were assessed. The median SBP was 128.5 (112.0–146.0) mm Hg, mean eGFR was 50.8 ± 23.7 mL/min/1.73 m2, and median NT-proBNP was 2,183 (IQR 1,010–5,310) pg/mL. Overall, 155 (32.4%) patients had LVEF ≤40%. According to the DAPA-HF trial key criteria, 90 patients (18.8%) would be eligible for dapagliflozin. The remainder would be excluded due to LVEF >40% (67.6%), eGFR <30 mL/min/1.73 m2 (19.4%), NT-proBNP below the cutoff (16.7%), and/or SBP <95 mm Hg (6.5%). If we center the analysis to those with LVEF ≤40%, 58.1% would be eligible for dapagliflozin. The remainder would be excluded due to an eGFR <30 mL/min/1.73 m2 (20%), NT-proBNP below the cutoff (16.1%), and/or SBP <95 mm Hg (8.4%). Conclusion: Roughly half of our real-world HFrEF cohort would be eligible for dapagliflozin according to the key criteria of the DAPA-HF trial. The main reason for non-eligibility was an eGFR <30 mL/min/1.73 m2. However, two-thirds of patients had LVEF >40%. These findings show that dapagliflozin is a promising complementary new drug in the therapeutic armamentarium of most patients with HFrEF, while highlighting the urgent need for disease-modifying drugs in mid-range and preserved LVEF and the need to assess the efficacy and safety of SLGT2i in advanced kidney disease patients. The results of ongoing SGLT2i trials in these LVEF subgroups are eagerly awaited.

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Effects of SGLT2 inhibitor dapagliflozin in patients with heart failure with reduced ejection fraction

Russian Journal of Cardiology ◽

10.15829/1560-4071-2020-4049 ◽

2020 ◽

Vol 25 (8) ◽

pp. 4049

Author(s):

N. R. Khasanov

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Drug Class ◽

Sglt2 Inhibitor ◽

Cardiovascular Death ◽

Sglt2 Inhibitors ◽

Reduced Ejection Fraction ◽

Patients With Heart Failure ◽

Recommended Therapy

SGLT2 inhibitors have been shown to reduce the risk of cardiovascular events and the development and decompensation of heart failure (HF) in patients with type 2 diabetes (T2D). The improved prognosis in HF may be related not only to the hypoglycemic effect of this drug class. The DAPA-HF study, which included patients with HF with reduced ejection fraction, demonstrated the benefit of dapagliflozin in reducing the risk of cardiovascular death and worsening HF, as well as improving HF symptoms compared to placebo, regardless of the presence of T2D and the recommended therapy for HF.

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Estimated Population Prevalence of Heart Failure with Reduced Ejection Fraction in Spain, According to DAPA-HF Study Criteria

Journal of Clinical Medicine ◽

10.3390/jcm9072089 ◽

2020 ◽

Vol 9 (7) ◽

pp. 2089

Author(s):

Anna Camps-Vilaró ◽

Juan F. Delgado-Jiménez ◽

Núria Farré ◽

Helena Tizón-Marcos ◽

Jesús Álvarez-García ◽

...

Keyword(s):

Heart Failure ◽

Ejection Fraction ◽

Sglt2 Inhibitor ◽

Heart Association ◽

Cardiovascular Effects ◽

Functional Class ◽

Adverse Outcomes ◽

Reduced Ejection Fraction ◽

Patient Profile ◽

Number Of Patients

Heart failure (HF) is one of the main causes of morbidity, mortality, and high healthcare costs. Dapagliflozin, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, reduced cardiovascular mortality and hospitalization for HF compared to placebo in patients with chronic HF, and reduced ejection fraction (EF) in the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) study. Our aim was to estimate the number of patients with DAPA-HF characteristics in Spain. Our literature review identified epidemiological studies whose objective was to quantify the prevalence of HF and its comorbidities in Spain. We estimated the prevalence of HF with reduced EF, of New York Heart Association (NYHA) functional class II–IV, and with a glomerular filtration rate (GFR) ≥ 30 mL/min/1.73 m². In this population, we analysed the prevalence of diabetes using data from the REDINSCOR (Spanish Network for Heart Failure) registry. Our estimations indicate there are 594,684 patients ≥45 years old with HF in Spain (2.6% of this population age group), of which 52.4%, 84.0%, and 93.9% have reduced EF, are NYHA II–IV, and have a GFR ≥ 30 mL/min/1.73 m², respectively. By our calculations, approximately 245,789 Spanish patients would meet the DAPA-HF patient profile, and therefore could benefit from the protective cardiovascular effects of dapagliflozin.

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