Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes

Abraham, William T.; Lindenfeld, JoAnn; Ponikowski, Piotr; Agostoni, Piergiuseppe; Butler, Javed; Desai, Akshay S.; Filippatos, Gerasimos; Gniot, Jacek; Fu, Michael; Gullestad, Lars; Howlett, Jonathan G.; Nicholls, Stephen J.; Redón, Josep; Schenkenberger, Isabelle; Silva-Cardoso, José; Störk, Stefan; Wranicz, Jerzy Krzysztof; Savarese, Gianluigi; Brueckmann, Martina; Jamal, Waheed; Nordaby, Matias; Peil, Barbara; Ritter, Ivana; Ustyugova, Anastasia; Zeller, Cordula; Salsali, Afshin; Anker, Stefan D.

doi:10.1093/eurheartj/ehaa943

Cited by 154 publications

(158 citation statements)

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“…The outcome of the 6MWT was reported in three studies (14,15,22), and we did not observe a significant difference between the two groups with regard to the distance change in the 6MWT before and after intervention [mean difference (MD): 34.06 (95% CI, −29.75-97.88); I 2 = 97%; P = 0.30; Figure 4].…”

Section: Six-minute Walk Testmentioning

confidence: 73%

“…Of the selected seven trials, 5,150 participants were included in total, 2,682 of them were in the empagliflozin group, and 2,468 of them were in the placebo group. Among them, six studies (11)(12)(13)(14)(15)22) were two-arm RCTs. The last was a three-arm RCT (21) comparing two different doses (10 and 25 mg) of empagliflozin with placebo, and it was also the only substudy of a previous trial (9).…”

Section: Study Characteristicsmentioning

confidence: 99%

“…The outcomes included a composite of cardiovascular death or hospitalization for worsening heart failure [three RCTs (11,12,21)], hospitalization for worsening heart failure [three RCTs (11,12,21)], change in KCCQ score [three RCTs (11,12,14)], change in NT-proBNP from baseline [five RCTs (11)(12)(13)(14)22)], change in 6MWT from baseline [three RCTs (14,15,22)], and change in body weight from baseline [four RCTs (11)(12)(13)15)].…”

Section: Study Characteristicsmentioning

confidence: 99%

“…The change from baseline of NT-proBNP was reported in five studies (11)(12)(13)(14)22), and no significant difference was observed between the two groups [MD: −98.36 (95% CI −225.83-29.11); I 2 = 68%; P = 0.13; Figure 5].…”

Section: Nt-probnpmentioning

confidence: 99%

“…Empagliflozin, one of the frequently used SGLT2i, has been proven to be effective in reducing HF hospitalizations, cardiovascular deaths, and biomarkers in patients with HF ( 11 ). However, the results in related articles showed heterogeneity in some outcomes, for example, N-terminal pro-brain natriuretic peptide (NT-proBNP) ( 12 , 13 ) and the 6-min walk test (6MWT) ( 14 , 15 ). The effect of empagliflozin in patients with HF has not been evaluated specifically.…”

Section: Introductionmentioning

confidence: 99%

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Empagliflozin in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Pan

Lin

Chen

et al. 2021

Front. Cardiovasc. Med.

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Purpose: The purpose of the study is to evaluate the effect of empagliflozin in patients with heart failure (HF).Method: We performed a systematic search of PubMed, EMBASE, and the Cochrane Library database through January 20, 2021. Randomized controlled trials (RCTs) were included that compared empagliflozin and placebo in patients with HF. Dichotomous variables were expressed as risk ratios (RRs) with 95% confidence intervals (CIs). Continuous variables were calculated and expressed as mean differences (MD) and standard deviation (SD). Meta-analysis was conducted using a random-effects model on outcomes with high heterogeneity.Results: Seven studies were included in our meta-analysis (n = 5,150). Significant differences were observed in a composite of cardiovascular death or hospitalization for worsening heart failure [RR: 0.77 (95% CI 0.68–0.87); I2 = 18%; P < 0.0001), hospitalization for worsening heart failure [RR: 0.71 (95% CI 0.61–0.82); I2 = 0%; P < 0.00001], changes in Kansas City Cardiomyopathy Questionnaire (KCCQ) score [MD: 1.70 (95% CI 1.67–1.73); I2 = 0%; P < 0.00001], and changes in body weight [MD: −1.43 (95% CI −2.15 to −0.72); I2 = 84%; P < 0.0001) from baseline. However, empagliflozin did not show a better change in the 6-min walk test (6MWT) [MD: 34.06 (95% CI −29.75–97.88); I2 = 97%; P = 0.30] or NT-proBNP [MD: −98.36 (95% CI, −225.83–29.11); I2 = 68%; P = 0.13] from baseline.Conclusion: The findings suggest that empagliflozin was effective in reducing a composite of cardiovascular death or hospitalization for worsening heart failure. Further well-designed RCTs are needed to evaluate the long-term effect of empagliflozin in patients with HF.PROSPERO: CRD42021231712.

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Section: Six-minute Walk Testmentioning

confidence: 73%

Section: Study Characteristicsmentioning

confidence: 99%

Section: Study Characteristicsmentioning

confidence: 99%

Section: Nt-probnpmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Empagliflozin in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Pan

Lin

Chen

et al. 2021

Front. Cardiovasc. Med.

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Quality of Life and Exercise Ability in Heart Failure With Preserved Ejection Fraction

Redfield

Borlaug

2021

JAMA

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The importance of HF with preserved ejection fraction (HFpEF) as a large subtype of HF has been recognized since the late 1980s. The quest for therapies that will reduce symptoms and improve quality of life for patients with HFpEF while helping them avoid hospitalization and live longer has been challenging. Most patients with HFpEF are older adults and have multiple comorbid conditions. Many such patients indicate a preference for a therapy that will improve quality of life even at some cost in quantity of life. 1 Remarkably, only this year has a large multinational clinical trial of a drug therapy shown unequivocal benefit for patients with HFpEF. In the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved), which included 5988 patients with HFpEF, treatment with the sodium glucose cotransporter-2 (SGLT2) inhibitor empagliflozin reduced the composite outcome of time to first HF hospitalization or cardiovascular death compared with placebo (absolute rates, 13.5% vs 20.1%, respectively; hazard ratio [HR], 0.79; 95% CI, 0.69-0.90; P < .001). 2 The improvement was primarily due to reduction in HF hospitalization, without benefit on mortality.However, as assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ) clinical summary score (range, 0-100; ≥5-point increase is considered clinically meaningful), there was no clinically meaningful benefit on quality of life, with only a 1.3-point (95% CI, 0.4-2.2) difference with empagliflozin vs placebo. 1 This finding was consistent with another study that included 315 patients with HFpEF and demonstrated no effect of empagliflozin on the KCCQ score or on 6-minute walk distance. 3 A more recent trial with dapagliflozin that involved 324 patients with HFpEF identified improvement in both KCCQ score (difference, 5.8; 95% CI, 2.3-9.2; P < .001 vs placebo) and the 6-minute walk distance (difference, 20.1 m; 95% CI, 5.6 vs 34.7; P = .007 vs placebo) after 12 weeks of therapy. 4 A larger trial (enrollment complete at 6263 patients) testing the effect of dapagliflozin on HF hospitalization and cardiovascular death, as well as on quality of life at 8 months, in HFpEF is ongoing (NCT03619213).Prior to the EMPEROR-Preserved trial, 2 other clinical trials contributed to the evidence base for therapeutic decision-making in HFpEF. In the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial, 5 which involved 3445 patients with HFpEF, the number of patients who experienced the primary

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Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction

Pieske

Wachter

Shah

et al. 2021

JAMA

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IMPORTANCEThere is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%).OBJECTIVE To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%. DESIGN, SETTING, AND PARTICIPANTSA 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019).INTERVENTIONS Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor.MAIN OUTCOMES AND MEASURES Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks. RESULTS Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, −2.5 m; 95% CI, −8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, −0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%).CONCLUSIONS AND RELEVANCE Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibito...

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Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes

Cited by 154 publications

References 26 publications

Empagliflozin in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Empagliflozin in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Quality of Life and Exercise Ability in Heart Failure With Preserved Ejection Fraction

Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction

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